DHA-pharmaceutical agent conjugates of taxanes

ABSTRACT

The invention provides conjugates of cis-docosahexaenoic acid and pharmaceutical agents useful in treating noncentral nervous system conditions. Methods for selectively targeting pharmaceutical agents to desired tissues are provided.

RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.09/846,838 filed May 1, 2001, now U.S. Pat. No. 6,602,902, which is acontinuation of U.S. patent application Ser. No. 09/135,291 filed Aug.17, 1998, now abandoned, which is a continuation of U.S. patentapplication Ser. No. 08/651,312, filed May 22, 1996, now U.S. Pat. No.5,795,909.

BACKGROUND OF THE INVENTION

Improving drug selectivity for target tissue is an established goal inthe medical arts. In general, it is desirable to deliver a drugselectively to its target, so that dosage and, consequently, sideeffects can be reduced. This is particularly the case for toxic agentssuch as anti-cancer agents because achieving therapeutic doses effectivefor treating the cancer is often limited by the toxic side effects ofthe anti-cancer agent on normal, healthy tissue. The problems relatingto lack of drug selectivity can be exemplified by Taxol®.

Taxol® (paclitaxel) was first isolated in 1971 from the bark of Taxusbrevifolia and was approved in 1992 by the US Food and DrugAdministration for treatment of metastatic ovarian cancer and later forbreast cancer. Its mechanism of action is believed to involve promotingformation and hyperstabilization of microtubules, thereby preventing thedisassembly of microtubules necessary for completion of cell division.It also has been reported that Taxol induces expression of cytokines,affects the activity of kinases and blocks processes essential formetastasis, in as yet uncharacterized mechanisms of action.

Taxol has attracted unusually strong scientific attention, not onlybecause of its unique antiproliferative mechanism of action, but alsobecause it is active against nearly all cancers against which it hasbeen tested and because it has been discovered to be an analog ofnumerous closely related compounds occurring naturally. These compounds,taxanes, are now recognized as a new class of anticancer compounds.

Taxol's strength against cancers of diverse tissue origin alsorepresents a significant drawback. An ideal anticancer agent has tissuespecificity, thereby reducing side-effects on normal (dividing) cells.Taxol analogs with tissue specificity therefore are desired. Anotherdrawback of Taxol is its extreme insolubility. Taxol can be administeredeffectively in a solvent including cremophor, which combination canprovoke severe hypersensitive immune responses. As a result of thesedrawbacks, and also as a result of the potential for modifying Taxol atnumerous sites as demonstrated by other naturally-occurring taxanes withanticancer activity, a search for more selective taxanes was launched.

To date, more than 200 taxanes have been synthesized (or isolated) andtested in vitro or in vivo for anticancer activity. The results,however, have been so disappointing that the National Cancer Institute(NCI) generally no longer is interested in testing Taxol analogs. Ingeneral with Taxol analogs, the solubility problems remain, and/orpotency is sharply reduced, and/or selectivity is not improved, and/orthe ratio of the median toxic dose to the median effective dose(“therapeutic index”) is unacceptably reduced.

Taxol has the following formula:

Taxanes have the basic three ring structure (A, B and C), substituted orunsubstituted.

Taxol's carbons are numbered conventionally as follows:

Based upon the taxanes tested to date, as many questions have beenraised as have been answered, and general rules have not been fashionedeasily in predicting selectivity, activity and solubility. Firstly, norules have emerged regarding selectivity. Those taxanes that arestrongly active appear to have activity as broad as Taxol's activity,and no headway appears to have been made in terms of developing a moreselective Taxol analog.

Some information about activity has emerged. Numerous substitutions havebeen made at C7, C9, C10, C19, R₁ and combinations thereof whileretaining significant, but usually reduced, activity. Substitutions atC2, C4 and 2′OH, however, are generally not tolerated. These conclusionsare only generalities, for example, because some substitutions at C9–C10(cyclic derivatives) are not tolerated and some substitutions at C2(meta substitutions on the phenyl) are tolerated. Likewise, the C13 sidechain and, in particular, the 2′OH are required although the minimumstructural requirements of the side chain have not been determined fortherapeutic efficacy.

Attempts to improve Taxol's solubility have not resulted in successfulclinical products. One approach has been to manufacture prodrugs ofTaxol, which prodrugs undergo in vivo transformation into Taxol and someother product. Attempts were made to esterify the C7 hydroxy and 2′hydroxy groups, with the hope that the bond would be stable in solution(to permit preferred administration modes—i.v. over at least 24 hours)but would cleave readily in vivo. The groups tested were all hydrophilicand included amines, short carboxylic acids (using e.g. succinicanhydride and glutaric anhydride), sulfonic acids, amino acids andphosphates. Generally, activity was reduced although some success wasobtained with certain derivatives. Again, no particular pattern emergedpermitting one to predict reliably which groups could be substituted onTaxol to yield a therapeutically useful product, although it wassuggested that the 2′ OH derivatives may cleave more easily than the C7OH derivatives.

Several other factors add to the problem of predicting which Taxolanalogs will be effective. Multiple mechanisms of action have beenproposed in the literature and a change in one position may have noeffect on activity on one such mechanism but may eliminate activity onanother mechanism. In addition, changes that favorably influenceactivity may unfavorably influence bioavailability. For example, Taxolaffects microtubule formation inside a cell, but a change in structurethat increases intracellular activity may adversely affect the abilityof Taxol to gain entry into a cell. Taxol also is known to bind toproteins, and the effect on activity that results from a change inTaxol's binding to protein (in terms of conformation. cellularabsorption and solubility) is unknown.

It has been reported that Taxol does not get into the brain, apparentlyexcluded by the blood brain barrier. It is not known why this is so, asTaxol is lipophilic, gets into cells and might be expected to cross theblood brain barrier.

Among the most promising of the two hundred analogs tested is Taxotere(docetaxel), because of its slightly increased activity and solubility.Oddly, however, Taxotere differs from Taxol at sites which typically donot have a strong influence on activity, and one would not predict theimprovements in Taxotere from these differences, even in hindsight.

Taxotere has the following formula:

DHA (docosahexaenoic acid) is a 22 carbon naturally-occurring,unbranched fatty acid that previously has been attached to drugs to helpdeliver them across the blood brain barrier. DHA is attached via theacid group to hydrophilic drugs and renders these drugs more hydrophobic(lipophilic). DHA is an important constituent of the brain and recentlyhas been approved in Europe as an additive to infant formula. It ispresent in the milk of lactating women. The mechanism of action by whichDHA helps drugs conjugated to it cross the blood brain barrier isunknown.

SUMMARY OF THE INVENTION

The present invention involves the unexpected finding that conjugates ofpharmaceutical agents and a highly lipphilic group, a C22 unbranchedcarbon chain, have a different selectivity relative to the unconjugatedpharmaceutical agents. The conjugates, in general, render the activityof these compounds selective for colon tissue, breast tissue and centralnervous system tissue (“targeted tissues”). The conjugates, alsounexpectedly, restrict the activity of these compounds to cell typeswithin these tissue categories relative to that of the unconjugatedpharmaceutical agents. The conjugates, further unexpectedly, reducesharply the activity of these compounds relative to that of theunconjugated pharmaceutical agents in most cell lines of tissue typesother than colon, breast, and central nervous system, thereby reducingpotential side effects of the conjugates versus those of theunconjugated pharmaceutical agents. The therapeutic index of theconjugates may be improved, versus that of the unconjugatedpharmaceutical agents.

According to one aspect of the invention, a method is provided fortargeting a pharmaceutical agent to a noncentral nervous system tissueto treat a noncentral nervous system condition. A covalent conjugate ofcis-docosahexanoic acid and a pharmaceutical agent effective fortreating said condition is administered to a subject in need of suchtreatment. In preferred embodiments, the tissue is breast tissue,gastrointestinal tissue and ovarian tissue and the condition calls fortreatment of breast tissue, gastrointestinal tissue or ovarian tissue,respectively.

The pharmaceutical agent may be any pharmacological compound ordiagnostic agent, as desired. The pharmaceutical agent, of course, hasan activity outside of the central nervous system.

Examples of categories of pharmaceutical agents include: adrenergicagent; adrenocortical steroid; adrenocortical suppressant; alcoholdeterrent; aldosterone antagonist; amino acid; ammonia detoxicant;anabolic; analeptic; analgesic; androgen; anesthesia, adjunct to;anesthetic; anorectic; antagonist; anterior pituitary suppressant;anthelmintic; anti-acne agent; anti-adrenergic; anti-allergic;anti-amebic; anti-androgen; anti-anemic; anti-anginal; anti-anxiety;anti-arthritic; anti-asthmatic; anti-atherosclerotic; antibacterial;anticholelithic; anticholelithogenic; anticholinergic; anticoagulant;anticoccidal; anticonvulsant; antidepressant; antidiabetic;antidiarrheal; antidiuretic; antidote; anti-emetic; anti-epileptic;anti-estrogen; antifibrinolytic; antifungal; antiglaucoma agent;antihemophilic; antihemorrhagic; antihistamine; antihyperlipidemia;antihyperlipoproteinemic; antihypertensive; antihypotensive;anti-infective; anti-infective, topical; anti-inflammatory;antikeratinizing agent; antimalarial; antimicrobial; antimigraine;antimitotic; antimycotic, antinauseant, antineoplastic, antineutropenic,antiobessional agent; antiparasitic; antiparkinsonian; antiperistaltic,antipneumocystic; antiproliferative; antiprostatic hypertrophy;antiprotozoal; antipruritic; antipsychotic; antirheumatic;antischistosomal; antiseborrheic; antisecretory; antispasmodic;antithrombotic; antitussive; anti-ulcerative; anti-urolithic; antiviral;appetite suppressant; benign prostatic hyperplasia therapy agent; bloodglucose regulator; bone resorption inhibitor; bronchodilator; carbonicanhydrase inhibitor; cardiac depressant; cardioprotectant; cardiotonic;cardiovascular agent; choleretic; cholinergic; cholinergic agonist;cholinesterase deactivator; coccidiostat; cognition adjuvant; cognitionenhancer; depressant; diagnostic aid; diuretic; dopaminergic agent;ectoparasiticide; emetic; enzyme inhibitor; estrogen; fibrinolytic;fluorescent agent; free oxygen radical scavenger; gastrointestinalmotility effector; glucocorticoid; gonad-stimulating principle; hairgrowth stimulant; hemostatic; histamine H2 receptor antagonists;hormone; hypocholesterolemic; hypoglycemic; hypolipidemic; hypotensive;imaging agent; immunizing agent; immunomodulator; immunoregulator;immunostimulant; immunosuppressant; impotence therapy adjunct;inhibitor; keratolytic; LNRH agonist; liver disorder treatment;luteolysin; memory adjuvant; mental performance enhancer; moodregulator; mucolytic; mucosal protective agent; mydriatic; nasaldecongestant; neuromuscular blocking agent; neuroprotective; NMDAantagonist; non-hormonal sterol derivative; oxytocic; plasminogenactivator; platelet activating factor antagonist; platelet aggregationinhibitor; post-stroke and post-head trauma treatment; potentiator;progestin; prostaglandin; prostate growth inhibitor; prothrotropin;psychotropic; pulmonary surface; radioactive agent; regulator; relaxant;repartitioning agent; scabicide; sclerosing agent; sedative;sedative-hypnotic; selective adenosine A1 antagonist; serotoninantagonist; serotonin inhibitor; serotonin receptor antagonist; steroid;stimulant; suppressant; symptomatic multiple sclerosis; synergist;thyroid hormone; thyroid inhibitor; thyromimetic; tranquilizer;treatment of amyotrophic lateral sclerosis; treatment of cerebralischemia; treatment of Paget's disease; treatment of unstable angina;uricosuric; vasoconstrictor; vasodilator; vulnerary; wound healingagent; xanthine oxidase inhibitor.

In one particularly preferred embodiment of the invention, thepharmaceutical agent is an anti-cancer agent. Examples of anti-canceragents are described in greater detail in the specification. Includedspecifically are the taxanes (e.g., Taxol and Taxotere). Conjugates ofcis-docosahexanoic acid and taxoids also are embraced by the invention.

Cis-docosahexanoic acid previously has been conjugated to drugs that areactive in the central nervous system. The present invention contemplatesthe use of cis-docosahexanoic acid in the manufacture of a medicamentfor treating a noncentral nervous system condition. The inventionfurther contemplates compositions of matter that are covalent conjugatesof cis-docosahexanoic acid and noncentral nervous system activepharmaceutical agents. A noncentral nervous system active pharmaceuticalagent is one that has no function or use in the central nervous system.Its only therapeutic use is outside of the central nervous system.Examples of such agents include, but are not limited to: Blood glucoseregulators, such as tolazamide, tolbutamide, chlorpropamide,acetohexamide, and, glipizide; HMGcoA reductase inhibitors, such asLovastatin (Mevacor), Simvastatin (Zocor), Pravastatin (Pravachol), and,Fluvstatin (Lescol); Muscosal Protectives, such as Misoprostol(Cytotec); Gastrointestinal motility affectors, such as Cisapride(Propulsid), Metoclopramide (Reglan), and, Hyoscyamine (Levsin);Antidiarrheals, such as Diphenoxylate hydrochloride (Lomotil),Metronidazole (Flagyl), Methylprednisolone (Medrol), and, Sulfasalazine(Azulfidine); and Hormones for treating, inter alia, ovarian conditions,such as Progesterone, Norgestrel, Norethynodrel, Norethindrone,Levonorgestrel, Ethyndiol, Mestranol, Estrone, Equilin, 17 alphadihydroequilin, equilenin, 17 alpha dihydroequilenin, 17 alpha esradiol,27 bea estradiol, Leuprolide (Lupron), Testolactone, Climiphene,urofollitropin, bromocriptine, gonadorelin, danazol,dehydroepiandrosterone, androstenedione, dihydrotestosterone, Relaxin,folliculostatin, Follicle regulatory protein, Gonadocrinins, Oocytematuration inhibitor, and, Insulin growth factor. Other compounds aredetailed below.

The methods and/or products of the invention are useful for treating avariety of medical conditions including conditions involving abnormalmammalian-cell proliferation. They further are useful in treatingdiabetes and its complications, excess acid secretion, cardiovascularconditions involving cholesterol (e.g., hyperlipidemia andhypercholesterolemia), diarrhea, ovarian diseases (e.g. endometriosis,ovarian cysts, etc.) and as contraceptive agents. Other conditionstreatable according to the invention will be apparent to those skilledin the art based upon the disclosure and lists of compounds provided.

The methods and/or products of the invention also are useful in treatingconditions specific to noncentral nervous system tissue. Such conditionscan be specific to breast tissue, gastrointestinal tissue and ovariantissue. The tissue also may be other noncentral nervous system tissues.Noncentral nervous system tissue includes tissue of the: Blood and BloodForming system: including platelets, blood vessel wall, and bone marrow;Cardiovascular system: including heart and vascular system; Digestiveand excretory system: including alimentary tract, biliary tract, kidney,liver, pancreas and urinary tract; Endocrine system: including adrenalgland, kidney, ovary, pituitary gland, renal gland, salivary gland,sebaceous gland, testis, thymus gland and thyroid gland; Muscularsystem: including muscles that move the body. Reproductive System:including breast, ovary, penis and uterus; Respiratory system: includingbronchus, lung and trachea; Skeletal system: including bones and joints;Tissue, fiber, and integumentary system: including adipose tissue,cartilage, connective tissue, cuticle, dermis, epidermis, epithelium,fascia, hair follicle, ligament, bone marrow, melanin, melanocyte,mucous membrane, skin, soft tissue, synovial capsule and tendon.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph plotting concentration of conjugate 1 versus percentgrowth of leukemia cells.

FIG. 2 is a graph plotting concentration of conjugate 1 versus percentgrowth of non-small cell lung cancer cells.

FIG. 3 is a graph plotting concentration of conjugate 1 versus percentgrowth of colon cancer cells.

FIG. 4 is a graph plotting concentration of conjugate 1 versus percentgrowth of CNS cancer cells.

FIG. 5 is a graph plotting concentration of conjugate 1 versus percentgrowth of melanoma cells.

FIG. 6 is a graph plotting concentration of conjugate 1 versus percentgrowth of ovarian cancer cells.

FIG. 7 is a graph plotting concentration of conjugate 1 versus percentgrowth of renal cancer cells.

FIG. 8 is a graph plotting concentration of conjugate 1 versus percentgrowth of prostate cancer cells.

FIG. 9 is a graph plotting concentration of conjugate 1 versus percentgrowth of breast cancer cells.

FIG. 10 is a graph plotting concentration of conjugate 2 versus percentgrowth of leukemia cells.

FIG. 11 is a graph plotting concentration of conjugate 2 versus percentgrowth of non-small cell lung cancer cells.

FIG. 12 is a graph plotting concentration of conjugate 2 versus percentgrowth of colon cancer cells.

FIG. 13 is a graph plotting concentration of conjugate 2 versus percentgrowth of CNS cancer cells.

FIG. 14 is a graph plotting concentration of conjugate 2 versus percentgrowth of melanoma cells.

FIG. 15 is a graph plotting concentration of conjugate 2 versus percentgrowth of ovarian cancer cells.

FIG. 16 is a graph plotting concentration of conjugate 2 versus percentgrowth of renal cancer cells.

FIG. 17 is a graph plotting concentration of conjugate 2 versus percentgrowth of prostate cancer cells.

FIG. 18 is a graph plotting concentration of conjugate 2 versus percentgrowth of breast cancer cells.

FIG. 19 is a graph plotting concentration of Taxol versus percent growthof leukemia cells.

FIG. 20 is a graph plotting concentration of Taxol versus percent growthof non-small cell lung cancer cells.

FIG. 21 is a graph plotting concentration of Taxol versus percent growthof colon cancer cells.

FIG. 22 is a graph plotting concentration of Taxol versus percent growthof CNS cancer cells.

FIG. 23 is a graph plotting concentration of Taxol versus percent growthof melanoma cells.

FIG. 24 is a graph plotting concentration of Taxol versus percent growthof ovarian cancer cells.

FIG. 25 is a graph plotting concentration of Taxol versus percent growthof renal cancer cells.

FIG. 26 is a graph plotting concentration of Taxol versus percent growthof prostate cancer cells.

FIG. 27 is a graph plotting concentration of Taxol versus percent growthof breast cancer cells.

DETAILED DESCRIPTION OF THE INVENTION

cis-docosahexaenoic acid (DHA) is a naturally occurring fatty acid. Itis an unbranched chain fatty acid with six double bonds, all cis. Itsstructure is as follows:

DHA can be isolated, for example, from fish oil or can be chemicallysynthesized. These methods, however, can generate trans isomers, whichare difficult and expensive to separate and which may present safetyproblems in humans. The preferred method of production is biologicalsynthesis to produce the all cis isomer. The preferred source of DNA isfrom Martek Biosciences Corporation of Columbia, Md. Martek has apatented system for manufacturing DHA using microalgae which synthesizeonly a single isomer of DHA, the all cis isomer. Martek's patentsinclude U.S. Pat. Nos. 5,374,657, 5,492,938; 5,407,957 and 5,397,591.

DHA also is present in the milk of lactating women, and Martek'slicensee has obtained approval in Europe of DHA as a nutritionalsupplement for infant formula.

It is known that DHA can be unstable in the presence of oxygen. Tostabilize DHA and its conjugates it is important to add anti-oxidants tothe material after it is synthesized. One method of stabilization is tomake-up the newly synthesized material in the following solution: 100 gneat DHA-taxol plus 100 g of vehicle (100 ml propylene glycol, 70 mgalph-tocopherol, 5 mg dialaurylthiodipropionic acid, 50 mg ascorbicacid) prepared and held under argon in amber, sealed vials and stored atfour degrees centigrade. The following anti-oxidants may also beemployed: ascorbic acid, ascorbyl palmitate, dilauryl ascorbate,hydroquinone, butylated hydroxyanisole, sodium meta bisulfite, t-Bcarotene and x-tocopherol. A heavy metal chelator such asethylenediamine tetra-acetic acid (EDTA) may also be used.

Paclitaxel was first isolated from the bark of Taxus brevifolia (Wani etal., J. Am. Chem. Soc., 93, 2325, 1971). Its isolation and synthesishave been reported extensively in the literature. Applicants obtainedpaclitaxel from a commercial source, Hauser Laboratories, of Boulder,Colo.

EXAMPLE 1

A solution of Taxol (41 μmol) in methylene chloride (2.5 mL) under argonwas mixed with 4-dimethylaminopyridine (41 μmol),dicyclohexylcarbodiimide (82 μmol), and DHA (41 μmol) and the reactionmixture was stirred at ambient temperature for two hours. Followingdilution with ether, the reaction mixture was washed with 5%hydrochloric acid, water, saturated aqueous sodium chloride, dried, andconcentrated. Radial chromatography of the residue produced 45 mg (94%)of crystalline Taxol-DHA conjugate 1.

EXAMPLE 2

The production of analog 2 involves several steps including a number ofprotection-acylation-deprotection steps. A solution of Taxol (59 μmol)in methylene chloride (2.5 mol) was mixed at ambient temperature underargon with imidazole (147 μmol) and triethylsilyl chloride (147 μmol).The reaction mixture was stirred for thirty minutes, diluted withadditional methylene chloride, washed with water, saturated aqueoussodium chloride, dried, and concentrated. Chromatography of the residueproduced 50 mg (88%) of intermediate A plus 5 mg of the 2′,7-di(triethylsilyl) ether derivative. A solution of intermediate A (52μmol) in methylene chloride (3 mL) was mixed at ambient temperatureunder argon with 4-dimethylaminopyridine (52 μmol),dicyclohexylcarbodiimide (104 μmol), and DHA (52 μmol). The reactionmixture was stirred for ten hours, diluted with ether, passed throughcelite, and concentrated. Chromatography of the residue produced 65.9 mgof intermediate B. A solution of intermediate B (51 μmol) inacetonitrile (2 mL) at 0° C. under argon was mixed with 49% aqueous HF(0.2 mL) and the reaction mixture was stirred for one hour. Afterdilution with ether, the reaction mixture was washed with water,saturated aqueous sodium chloride, dried, and concentrated. Radialchromatography of the residue produced 44.6 mg (75%) of Taxol-DHAconjugate 2.

EXAMPLE 3

Conjugates 1 and 2 were sent to the United States National CancerInstitute (NCI) for screening in the NCI's anticancer screening program.The conjugates were provided in ethanol (approximately 40 mg analog/2 mlethanol). The conjugates were sealed in vials under argon to avoidexposure of the conjugates to oxygen because the conjugates werebelieved to be sensitive to oxygen. Instructions were provided to storeat 4° C. and to open the vials only when ready for immediateexperimental use. Instructions also were provided to use the ethanolsolutions containing the conjugates directly or to dissolve the analogsfurther in DMSO (dimethylsulfoxide) at appropriate concentrations, withvortexing if necessary for adequate dispersal.

The activities of conjugates 1 and 2 were tested against 57 cancer celllines. The results are presented in FIGS. 1–9 for conjugate 1, FIGS.10–18 for conjugate 2 and FIGS. 19–27 for Taxol. To understand the data,reference is made to the guides provided by the NCI, excerpted asfollows:

The Calculated Measurement of Effect: Percentage Growth (PG)

The measured effect of the compound on a cell line is currentlycalculated according to one or the other of the following twoexpressions:If (Mean OD _(test)−Mean OD _(tzero))≧0, thenPG=100×(Mean OD _(test)−Mean OD _(tzero))/(Mean OD _(ctrl)−Mean Od_(tzero))If (Mean OD _(test)−Mean OD _(tzero))<0, thenPG=100×(Mean OD _(test)−Mean Od _(tzero))/Mean Od _(tzero)Where:

-   Mean OD_(tzero)=The average of optical density measurements of    SRB-derived color just before exposure of cells to the test    compound.-   Mean OD_(test)=The average of optical density measurements of    SRB-derived color after 48 hours exposure of cells to the test    compound.-   Mean OD_(ctrl)=The average of optical density measurements of    SRB-derived color after 48 hours with no exposure of cells to the    test compound.    -   Experimental data was collected against each cell line . . .        Each concentration is expressed as the log₁₀ (molar or μg/ml) .        . . The response parameters GI50, TGI, and LC50 are interpolated        values representing the concentrations at which the PG is +50,        0, and −50, respectively. Sometimes these response parameters        cannot be obtained by interpolation. If, for instance, all of        the PGs in a given row exceed +50, then none of the three        parameters can be obtained by interpolation. In such a case, the        value given for each response parameter is the highest        concentration tested . . . This practice is extended similarly        to the other possible situations where a response parameter        cannot be obtained by interpolation.

Dose-Response Curves:

-   -   The dose-response curve page of the data package is created by        plotting the PGs against the log₁₀ of the corresponding        concentration for every cell line. The cell line curves are        grouped by subpanel. Horizontal lines are provided at the PG        values of +50, 0, and −50. The concentrations corresponding to        points where the curves cross these lines are the GI50, TGI and        LC50, respectively.

Several important distinctions are apparent from the data. Mostimportant, the patterns of anticancer actively for conjugates 1 and 2differ from that of Taxol. In one sense, conjugates 1 and 2 areeffective anticancer agents against a more restricted set of cancer celllines. For example, conjugates 1 and 2 were not very effective againstany of the six leukemia cancer cell lines tested, whereas Taxol wassomewhat effective against all four leukemia cell lines against whichTaxol was tested. (See FIGS. 1, 10 and 19.)

The relative activity against members within a class of cancers also wasaltered. For example, at TGI (horizontal line at zero in the graphs),Taxol was more effective against non-small cell lung cancer line H522than against H460 (by about 3 logs), whereas conjugates 1 and 2 wereslightly more effective against H460 than H522. As another example,Taxol was least effective at TGI against CNSU251, whereas conjugate 1was most effective against CNSU251 and conjugates 2 was also veryeffective against CNSU251 (relative to other CNS cell lines). As afurther example, Taxol was equivalent in activity toward MDA-N andMDA-MB-435 breast cancer cell lines at all concentrations tested,whereas conjugates 1 and 2 were more effective against MDA-N thanMDA-MB-435 at all concentrations tested.

To further illustrate the differences in the activity of conjugates 1and 2 versus that of Taxol, the NCI subjected the data to a statisticalanalysis designed by the NCI to reflect differences in the pattern ofactivity of anticancer agents. Conjugate 1 and conjugate 2 weredetermined to be statistically different in their pattern of activityversus Taxol in this unique measurement by the NCI.

It also is to be noted that, in general, conjugates 1 and 2 were onethousand to ten thousand times less potent than Taxol for many celllines tested. This reduction in activity is important, especially sinceconjugates 1 and 2 maintained strong activity against some cell lines.Conjugates 1 and 2 will be sufficiently active against certain celllines, but will have, on average, a substantially and disproportionatelylower activity against other cell lines, reducing potential sideeffects. For example, the TGI for Taxol against CNS SF-539 is −6.95, andthe TGI for conjugate 1 against this cell line is −5.13 and forconjugate 2 is −5.53. (In other words, the activity of the conjugateswas reduced versus that of Taxol by less than 2 logs). The GI50 forTaxol against CNS SF 539 is −7.52, whereas the GI50s for conjugates 1and 2 are −6.22 and −5.56, respectively (again less than 2 logsdifference). In contrast, Taxol has a GI50 for cell line CNSSF 268 ofless than −10.0, whereas conjugates 1 and 2 have GI50s for CNSSF 268 of5.36 and 5.28, respectively. This represents a reduction of activity inthe conjugates vs. that of Taxol by at least about 5 logs activity! Onaverage, the GI50 for Taxol across all cell lines tested is at least−9.19. (It is probably much higher since concentrations less than −10were not tested, and if Taxol was active at −10.0, −10 (instead of theactual lower value) was used in calculating the average of −9.19. Therewere 27 instances when this occurred.) The average GI50s for conjugates1 and 2, on the other hand, were 5.49 and 5.22, respectively. Therefore,the average difference in activity for Taxol vs. the conjugates is atleast between 3 and 4 logs. Thus, the sharp reduction in the activity ofthe conjugates against many cell lines vs. a lesser reduction for othercell lines is expected to reduce the potential side effects of theconjugates versus those of Taxol at effective doses.

Cancers other than CNS, breast and colon cancer can be treated. Forexample, there was activity against non-small cell lung cancer cells,melanoma cells and ovarian cancer cells. However, the activity wasrelatively reduced and was extremely specific, limiting the utility ofthe conjugates for treating generally such cancers. In any event, cancerpatients could be evaluated to determine if a conjugate is stronglyactive against the patient's cancer prior to selecting the conjugate asthe anti-cancer agent of choice for that patient.

The foregoing experiments establish that DHA analogs have alteredspecificity versus that of Taxol for cancer cell lines. Because of thisaltered specificity, it also is clear that the conjugates themselves aregaining access into the target cells (as opposed to simply releasingTaxol into the environment outside of the cell). Thus, the DHA moietyappears to selectively target certain cell types as opposed to others.The ability of the conjugates to gain entry into the cells was unknownprior to the invention, and the ability of the DHA moiety to selectivelytarget certain cell types was unexpected.

The same is true of DHA-Taxotere covalent conjugates, examples of whichare presented below. Taxotere's synthesis has been reported extensivelyin the literature. One example is Kanazawa, A. et al., J. Organic Chem.1994, Vol. 59, pp. 1238–1240.

EXAMPLE 4

A solution of Taxotere in methylene chloride under argon is mixed with4-dimethylaminopyridine, dicyclohexylcarbodiimide, and DHA. The reactionmixture is stirred at ambient temperature. Radial chromatography of theresidue is performed to produce Taxotere-DHA conjugate 3.

EXAMPLE 5

A solution of Taxotere in dimethylformamide is mixed at ambienttemperature under argon with imidazole and triethylsilyl chloride. Thereaction mixture is stirred at ambient temperature, diluted withmethylene chloride, washed with water, saturated aqueous'sodiumchloride, dried, and concentrated. Radial chromatography of the residueis performed to produce intermediate C. A solution of intermediate C inmethylene chloride is mixed at ambient temperature under argon with 4dimethylaminopyridine, dicyclohexylcarbodiimide, and DHA. The reactionmixture is stirred at ambient temperature, diluted with ether, passedthrough celite, and concentrated. Radial chromatography of the residueis performed to produce intermediate D. A solution of intermediate D inacetonitrile at 0° C. under argon is mixed with 49% aqueous HF and thereaction mixture is stirred at the same temperature. After dilution withether, the reaction mixture is washed with water, saturated aqueoussodium chloride, dried, and concentrated Radial chromatography of theresidue is performed to produce Taxotere-DHA conjugate 4.

EXAMPLE 6

A solution of Taxotere in dimethylformamide is mixed at ambienttemperature under argon with imidazole and tert-butylydimethylsilylchloride. The reaction mixture is stirred at ambient temperature,diluted with methylene chloride, washed with water, saturated aqueoussodium chloride, dried, and concentrated. Radial chromatography of theresidue is performed to produce intermediate E. A solution ofintermediate E in methylene chloride is mixed at ambient temperatureunder argon with 4-dimethylaminopyridine, dicyclohexylcarbodiimide, and1 equivalent of DHA. The reaction mixture is stirred at ambienttemperature, diluted with ether, passed through celite, andconcentrated. Radial chromatography of the residue is performed toproduce intermediate F. (Intermediate H also is obtained and used inExample 8 below.) A solution of intermediate F in acetonitrile at 0° C.under argon is mixed with aqueous HF and the reaction mixture is stirredat the same temperature. After dilution with ether, the reaction mixtureis washed with water, saturated aqueous sodium chloride, dried, andconcentrated Radial chromatography of the residue is performed toproduce Taxotere-DHA conjugate 4.

EXAMPLE 7

A solution of Taxotere in dimethylformamide is mixed at ambienttemperature under argon with imidazole and tert-butylydimethylsilylchloride. The reaction mixture is stirred at ambient temperature,diluted with methylene chloride, washed with water, saturated aqueoussodium chloride, dried, and concentrated. Radial chromatography of theresidue is performed to produce intermediate E. A solution ofintermediate E in methlylene chloride is mixed at ambient temperatureunder argon with 4-dimethylaminopyridine, dicyclohexylcarbodiimide, andDHA. The reaction mixture is stirred at ambient temperature, dilutedwith ether, passed through celite, and concentrated. Radialchromatography of the residue is performed to produce intermediate G. Asolution of intermediate G in acetonitrile at 0° C. under argon is mixedwith aqueous HF and the reaction mixture is stirred at the sametemperature. After dilution with ether, the reaction mixture is washedwith water, saturated aqueous sodium chloride, dried, and concentrated.Radial chromatography of the residue is performed to produceTaxotere-DHA conjugate 5.

EXAMPLE 8

A solution of taxotere in dimethylformamide is mixed at ambienttemperature under argon with imidazole and tert-butylydimethylsilylchloride. The reaction mixture is stirred at ambient temperature,diluted with methylene chloride, washed with water, saturated aqueoussodium chloride, dried, and concentrated. Radial chromatography of theresidue is performed to produce intermediate E. A solution ofintermediate E in methylene chloride is mixed at ambient temperatureunder argon with 4-dimethylaminopyridine, dicyclohexylcarbodiimide, and1 equivalent of DHA. The reaction mixture is stirred at ambienttemperature, diluted with ether, passed through celite, andconcentrated. Radial chromatography of the residue is performed toproduce intermediate H (and intermediate F which was used above onExample 6. A solution of intermediate H in acetonitrite at 0° C. underargon is mixed with aqueous HF and the reaction mixture is stirred atthe same temperature. After dilution with ether, the reaction mixture iswashed with water, saturated aqueous sodium chloride, dried, andconcentrated. Radial chromatography of the residue is performed toproduce Taxotere-DHA conjugate 6.

DHA may be conjugated to virtually any drug compound or diagnostic agentand used according to the methods of the present invention so long asthe pharmaceutical agent has a use outside of the central nervoussystem. Pharmaceutical agents include the following categories andspecific examples. It is not intended that the category be limited bythe specific examples. Those of ordinary skill in the art will be ableto identify readily those pharmaceutical agents that have utilityoutside of the central nervous system. Those of ordinary skill in theart will recognize also numerous other compounds that fall within thecategories and that are useful according to the invention.

-   Adrenergic: Adrenalone; Amidephrine Mesylate; Apraclonidine    Hydrochloride; Brimonidine Tartrate; Dapiprazole Hydrochloride;    Deterenol Hydrochloride; Dipivefrin; Dopamine Hydrochloride;    Ephedrine Sulfate; Epinephrine; Epinephrine Bitartrate; Epinephryl    Borate; Esproquin Hydrochloride; Etafedrine Hydrochloride;    Hydroxyamphetamine Hydrobromide; Levonordefrin; Mephentermine    Sulfate; Metaraminol Bitartrate; Metizoline Hydrochloride;    Naphazoline Hydrochloride; Norepinephrine Bitartrate; Oxidopamine;    Oxymetazoline Hydrochloride; Phenylephrine Hydrochloride;    Phenylpropanolamine Hydrochloride; Phenylpropanolamine Polistirex;    Prenalterol Hydrochloride; Propylhexedrine; Pseudoephedrine    Hydrochloride; Tetrahydrozoline Hydrochloride; Tramazoline    Hydrochloride; Xylometazoline Hydrochloride.-   Adrenocortical steroid: Ciprocinonide; Desoxycorticosterone Acetate;    Desoxycorticosterone Pivalate; Dexamethasone Acetate;    Fludrocortisone Acetate; Flumoxonide; Hydrocortisone Hemisuccinate;    Methylprednisolone Hemisuccinate; Naflocort; Procinonide; Timobesone    Acetate; Tipredane.-   Adrenocortical suppressant: Aminoglutethimide; Trilostane.-   Alcohol deterrent: Disulfiram.-   Aldosterone antagonist: Canrenoate Potassium; Canrenone; Dicirenone;    Mexrenoate Potassium; Prorenoate Potassium; Spironolactone.    Amino acid: Alanine; Aspartic Acid; Cysteine Hydrochloride; Cystine;    Histidine; Isoleucine; Leucine; Lysine; Lysine Acetate; Lysine    Hydrochloride; Methionine; Phenylalanine; Proline; Serine;    Threonine; Tryptophan; Tyrosine; Valine.-   Ammonia detoxicant: Arginine: Arginine Glutamate; Arginine    Hydrochloride.-   Anabolic: Bolandiol Dipropionate; Bolasterone; Boldenone    Undecylenate; Bolenol; Bolmantalate; Ethylestrenol; Methenolone    Acetate; Methenolone Enanthate; Mibolerone; Nandrolone Cyclotate;    Norbolethone; Pizotyline; Quinbolone; Stenbolone Acetate; Tibolone;    Zeranol.-   Analeptic: Modafinil.-   Analgesic: Acetaminophen; Alfentanil Hydrochloride; Aminobenzoate    Potassium; Aminobenzoate Sodium; Anidoxime; Anileridine; Anileridine    Hydrochloride; Anilopam Hydrochloride; Anirolac; Antipyrine;    Aspirin; Benoxaprofen; Benzydamine Hydrochloride; Bicifadine    Hydrochloride; Brifentanil Hydrochloride; Bromadoline Maleate;    Bromfenac Sodium; Buprenorphine Hydrochloride; Butacetin;    Butixirate; Butorphanol; Butorphanol Tartrate; Carbamazepine;    Carbaspirin Calcium; Carbiphene Hydrochloride; Carfentanil Citrate;    Ciprefadol Succinate; Ciramadol; Ciramadol Hydrochloride;    Clonixeril; Clonixin; Codeine; Codeine Phosphate; Codeine Sulfate;    Conorphone Hydrochloride; Cyclazocine; Dexoxadrol Hydrochloride;    Dexpemedolac; Dezocine; Diflunisal; Dihydrocodeine Bitartrate;    Dimefadane; Dipyrone; Doxpicomine Hydrochloride; Drinidene;    Enadoline Hydrochloride; Epirizole; Ergotamine Tartrate; Ethoxazene    Hydrochloride; Etofenamate; Eugenol; Fenoprofen; Fenoprofen Calcium;    Fentanyl Citrate; Floctafenine; Flufenisal; Flunixin; Flunixin    Meglurine; Flupirtine Maleate; Fluproquazone; Fluradoline    Hydrochloride; Flurbiprofen; Hydromorphone Hydrochloride; Ibufenac;    Indoprofen; Ketazocine; Ketorfanol; Ketorolac Tromethamine; Letimide    Hydrochloride; Levomethadyl Acetate; Levomethadyl Acetate    Hydrochloride; Levonantradol Hydrochloride; Levorphanol Tartrate;    Lofemizole Hydrochloride; Lofentanil Oxalate; Lorcinadol;    Lornoxicam; Magnesium Salicylate; Mefenamic Acid; Menabitan    Hydrochloride; Meperidine Hydrochloride; Meptazinol Hydrochloride;    Methadone Hydrochloride; Methadyl Acetate; Methopholine;    Methotrimeprazine; Metkephamid Acetate; Mimbane Hydrochloride;    Mirfentanil Hydrochloride; Molinazone; Morphine Sulfate; Moxazocine;    Nabitan Hydrochloride; Nalbuphine Hydrochloride; Nalmexone    Hydrochloride; Namoxyrate; Nantradol Hydrochloride; Naproxen;    Naproxen Sodium; Naproxol; Nefopam Hydrochloride; Nexeridine    Hydrochloride; Noracymethadol Hydrochloride; Ocfentanil    Hydrochloride; Octazamide; Olvanil; Oxetorone Fumarate; Oxycodone;    Oxycodone Hydrochloride; Oxycodone Terephthalate; Oxymorphone    Hydrochloride; Pemedolac; Pentamorphone; Pentazocine; Pentazocine    Hydrochloride; Pentazocine Lactate; Phenazopyridine Hydrochloride;    Phenyramidol Hydrochloride; Picenadol Hydrochloride; Pinadoline;    Pirfenidone; Piroxicam Olamine; Pravadoline Maleate; Prodilidine    Hydrochloride; Profadol Hydrochloride; Propiram Fumarate;    Propoxyphene Hydrochloride; Propoxyphene Napsylate; Proxazole;    Proxazole Citrate; Proxorphan Tartrate; Pyrroliphene Hydrochloride;    Remifentanil Hydrochloride; Salcolex; Salethamide Maleate;    Salicylamide; Salicylate Meglumine; Salsalate; Sodium Salicylate;    Spiradoline Mesylate; Sufentanil; Sufentanil Citrate; Talmetacin;    Talniflumate; Talosalate; Tazadolene Succinate; Tebufelone;    Tetrydamine; Tifurac Sodium; Tilidine Hydrochloride; Tiopinac;    Tonazocine Mesylate; Tramadol Hydrochloride; Trefentanil    Hydrochloride; Trolamine; Veradoline Hydrochloride; Verilopam    Hydrochloride; Volazocine; Xorphanol Mesylate; Xylazine    Hydrochloride; Zenazocine Mesylate; Zomepirac Sodium; Zucapsaicin.-   Androgen: Fluoxymesterone; Mesterolone; Methyltestosterone;    Nandrolone Decanoate; Nandrolone Phenpropionate; Nisterime Acetate;    Oxandrolone; Oxymetholone; Silandrone; Stanozolol; Testosterone;    Testosterone Cypionate; Testosterone Enanthate; Testosterone    Ketolaurate; Testosterone Phenylacetate; Testosterone Propionate;    Trestolone Acetate.-   Anesthesia, adjunct to: Sodium Oxybate.-   Anesthetic: Aliflurane; Benoxinate Hydrochloride; Benzocaine;    Biphenamine Hydrochloride; Bupivacaine Hydrochloride; Butamben;    Butamben Picrate; Chloroprocaine Hydrochloride; Cocaine; Cocaine    Hydrochloride; Cyclopropane; Desflurane; Dexivacaine; Diamocaine    Cyclamate; Dibucaine; Dibucaine Hydrochloride; Dyclonine    Hydrochloride; Enflurane; Ether; Ethyl Chloride; Etidocaine;    Etoxadrol Hydrochloride; Euprocin Hydrochloride; Fluroxene;    Halothane; Isobutamben; Isoflurane; Ketamine Hydrochloride;    Levoxadrol Hydrochloride; Lidocaine; Lidocaine Hydrochloride;    Mepivacaine Hydrochloride; Methohexital Sodium; Methoxyflurane;    Midazolam Hydrochloride; Midazolam Maleate; Minaxolone; Nitrous    Oxide; Norflurane; Octodrine; Oxethazaine; Phencyclidine    Hydrochloride; Pramoxine Hydrochloride; Prilocaine Hydrochloride;    Procaine Hydrochloride; Propanidid; Proparacaine Hydrochloride;    Propofol; Propoxycaine Hydrochloride; Pyrrocaine; Risocaine;    Rodocaine; Roflurane; Salicyl Alcohol; Sevoflurane; Teflurane;    Tetracaine; Tetracaine Hydrochloride; Thiamylal; Thiamylal Sodium;    Thiopental Sodium; Tiletamine Hydrochloride; Zolamine Hydrochloride.-   Anorectic compounds including dexfenfluramine.-   Anorexic: Aminorex; Amphecloral; Chlorphentermine Hydrochloride;    Clominorex; Clortermine Hydrochloride; Diethylpropion Hydrochloride;    Fenfluramine Hydrochloride; Fenisorex; Fludorex; Fluminorex;    Levamfetamine Succinate; Mazindol; Mefenorex Hydrochloride;    Phenmetrazine Hydrochloride; Phentermine; Sibutramine Hydrochloride.-   Antagonist: Atipamezole; Atosiban; Bosentan; Cimetidine; Cimetidine    Hydrochloride; Clentiazem Maleate; Detirelix Acetate; Devazepide;    Donetidine; Etintidine Hydrochloride; Famotidine; Fenmetozole    Hydrochloride; Flumazenil; Icatibant Acetate; Icotidine; Isradipine;    Metiamide; Nadide; Nalmefene; Nalmexone Hydrochloride; Naloxone    Hydrochloride; Naltrexone; Nilvadipine; Oxilorphan; Oxmetidine    Hydrochloride; Oxmetidine Mesylate; Quadazocine Mesylate;    Ranitidine; Ranitidine Bismuth Citrate; Ranitidine Hydrochloride;    Sufotidine; Teludipine Hydrochloride; Tiapamil Hydrochloride;    Tiotidine; Vapiprost Hydrochloride; Zaltidine Hydrochloride.-   Anterior pituitary activator: Epimestrol.-   Anterior pituitary suppressant: Danazol.-   Anthelmintic: Albendazole; Anthelmycin; Bromoxanide; Bunamidine    Hydrochloride; Butonate; Cambendazole; Carbantel Lauryl Sulfate;    Clioxanide; Closantel; Cyclobendazole; Dichlorvos;    Diethylcarbamazine Citrate; Dribendazole; Dymanthine Hydrochloride;    Etibendazole; Fenbendazole; Furodazole; Hexylresorcinol;    Mebendazole; Morantel Tartrate; Niclosamide; Nitramisole    Hydrochloride; Nitrodan; Oxantel Pamoate; Oxfendazole; Oxibendazole;    Parbendazole; Piperamide Maleate; Piperazine; Piperazine Citrate;    Piperazine Edetate Calcium; Proclonol; Pyrantel Pamoate; Pyrantel    Tartrate; Pyrvinium Pamoate; Rafoxanide; Stilbazium Iodide;    Tetramisole Hydrochloride; Thiabendazole; Ticarbodine; Tioxidazole;    Triclofenol Piperazine; Vincofos; Zilantel.-   Anti-acne: Adapalene; Erythromycin Salnacedin; Inocoterone Acetate.-   Anti-adrenergic: Acebutolol; Alprenolol Hydrochloride; Atenolol;    Bretylium Tosylate; Bunolol Hydrochloride; Carteolol Hydrochloride;    Celiprolol Hydrochloride; Cetamolol Hydrochloride; Cicloprolol    Hydrochloride; Dexpropranolol Hydrochloride; Diacetolol    Hydrochloride; Dihydroergotamine Mesylate; Dilevalol Hydrochloride;    Esmolol Hydrochloride; Exaprolol Hydrochloride; Fenspiride    Hydrochloride; Flestolol Sulfate; Labetalol Hydrochloride;    Levobetaxolol Hydrochloride; Levobunolol Hydrochloride; Metalol    Hydrochloride; Metoprolol; Metoprolol Tartrate; Nadolol; Pamatolol    Sulfate; Penbutolol Sulfate; Phentolamine Mesylate; Practolol;    Propranolol Hydrochloride; Proroxan Hydrochloride; Solypertine    Tartrate; Sotalol Hydrochloride; Timolol; Timolol Maleate;    Tiprenolol Hydrochloride; Tolamolol; Zolertine Hydrochloride.-   Anti-allergic: Amlexanox; Astemizole; Azelastine Hydrochloride;    Eclazolast; Minocrornil; Nedocromil; Nedocromil Calcium; Nedocromil    Sodium; Nivimedone Sodium; Pemirolast Potassium; Pentigetide;    Pirquinozol; Poisonoak Extract; Probicromil Calcium; Proxicromil;    Repirinast; Tetrazolast Meglumine; Thiazinamium Chloride;    Tiacrilast; Tiacrilast Sodium; Tiprinast Meglumine; Tixanox.-   Anti-amebic: Berythromycin; Bialamicol Hydrochloride; Chloroquine;    Chloroquine Hydrochloride; Chloroquine Phosphate; Clamoxyquin    Hydrochloride; Clioquinol; Emetine Hydrochloride; Iodoquinol;    Paromomycin Sulfate; Quinfamide; Symetine Hydrochloride; Teclozan;    Tetracycline; Tetracycline Hydrochloride.-   Anti-androgen: Benorterone; Cioteronel; Cyproterone Acetate;    Delmadinone Acetate; Oxendolone; Topterone; Zanoterone.-   Anti-anemic: Epoetin Alfa; Epoetin Beta; Ferrous Sulfate, Dried;    Leucovorin Calcium.-   Anti-anginal: Amlodipine Besylate; Amlodipine Maleate; Betaxolol    Hydrochloride; Bevantolol Hydrochloride; Butoprozine Hydrochloride;    Carvedilol; Cinepazet Maleate; Metoprolol Succinate; Molsidomine;    Monatepil Maleate; Primidolol; Ranolazine Hydrochloride; Tosifen;    Verapamil Hydrochloride.-   Anti-anxiety agent: Adatanserin Hydrochloride; Alpidem; Binospirone    Mesylate; Bretazenil; Glemanserin; Ipsapirone Hydrochloride;    Mirisetron Maleate; Ocinaplon; Ondansetron Hydrochloride;    Panadiplon; Pancopride; Pazinaclone; Serazapine Hydrochloride;    Tandospirone Citrate; Zalospirone Hydrochloride.-   Anti-arthritic: Lodelaben.-   Anti-asthmatic: Ablukast; Ablukast Sodium; Azelastine Hydrochloride;    Bunaprolast; Cinalukast; Cromitrile Sodium; Cromolyn Sodium;    Enofelast; Isamoxole; Ketotifen Fumarate; Levcromakalim; Lodoxamide    Ethyl; Lodoxamide Tromethamine; Montelukast Sodium; Ontazolast;    Oxarbazole; Oxatomide; Piriprost; Piriprost Potassium; Pirolate;    Pobilukast Edamine; Quazolast; Repirinast; Ritolukast; Sulukast;    Tetrazolast Meglumine; Tiaramide Hydrochloride; Tibenelast Sodium;    Tomelukast; Tranilast; Verlukast; Verofylline; Zarirlukast.-   Anti-atherosclerotic: Mifobate; Timefuronc.-   Antibacterial: Acedapsone; Acetosulfone Sodium; Alamecin; Alexidine;    Amdinocillin; Amdinocillin Pivoxil; Amicycline; Amifloxacin;    Amifloxacin Mesylate; Amikacin; Amikacin Sulfate; Aminosalicylic    acid; Aminosalicylate sodium; Amoxicillin; Amphomycin; Ampicillin;    Ampicillin Sodium; Apalcillin Sodium; Apramycin; Aspartocin;    Astromicin Sulfate; Avilamycin; Avoparcin; Azithromycin; Azlocillin;    Azlocillin Sodium; Bacampicillin Hydrochloride; Bacitracin;    Bacitracin Methylene Disalicylate; Bacitracin Zinc; Bambermycins;    Benzoylpas Calcium; Berythromycin; Betamicin Sulfate; Biapenem;    Biniramycin; Biphenamine Hydrochloride; Bispyrithione Magsulfex;    Butikacin; Butirosin Sulfate; Capreomycin Sulfate; Carbadox;    Carbenicillin Disodium; Carbenicillin Indanyl Sodium; Carbenicillin    Phenyl Sodium; Carbenicillin Potassium; Carumonam Sodium; Cefaclor;    Cefadroxil; Cefamandole; Cefamandole Nafate; Cefamandole Sodium;    Cefaparole; Cefatrizine; Cefazaflur Sodium; Cefazolin; Cefazolin    Sodium; Cefbuperazone; Cefdinir; Cefepime; Cefepime Hydrochloride;    Cefetecol; Cefixime; Cefmenoxime Hydrochloride; Cefmetazole;    Cefmetazole Sodium; Cefonicid Monosodium; Cefonicid Sodium;    Cefoperazone Sodium; Ceforanide; Cefotaxime Sodium; Cefotetan;    Cefotetan Disodium; Cefotiam Hydrochloride; Cefoxitin; Cefoxitin    Sodium; Cefpimizole; Cefpimizole Sodium; Cefpiramide; Cefpiramide    Sodium; Cefpirome Sulfate; Cefpodoxime Proxetil; Cefprozil;    Cefroxadine; Cefsulodin Sodium; Ceftazidime; Ceflibuten; Ceftizoxime    Sodium; Ceftriaxone Sodiumn; Cefuroxime; Cefuroxime Axetil;    Cefuroxime Pivoxetil; Cefuroxime Sodium; Cephacetrile Sodium;    Cephalexin; Cephalexin Hydrochloride; Cephaloglycin; Cephaloridine;    Cephalothin Sodium; Cephapirin Sodium; Cephradine; Cetocycline    Hydrochloride; Cetophenicol; Chloramphenicol; Chloramphenicol    Palmitate; Chloramphenicol Pantothenate Complex; Chloramphenicol    Sodium Succinate; Chlorhexidine Phosphanilate; Chloroxylenol;    Chlortetracycline Bisulfate; Chlortetracycline Hydrochloride;    Cinoxacin; Ciprofloxacin; Ciprofloxacin Hydrochloride; Cirolemycin;    Clarithromycin; Clinafloxacin Hydrochloride; Clindamycin;    Clindamycin Hydrochloride; Clindamycin Palmitate Hydrochloride;    Clindamycin Phosphate; Clofazimine; Cloxacillin Benzathine;    Cloxacillin Sodium; Cloxyquin; Colistimethate Sodium; Colistin    Sulfate; Coumermycin; Coumermycin Sodium; Cyclacillin; Cycloserine;    Dalfopristin; Dapsone; Daptomycin; Demeclocycline; Demeclocycline    Hydrochloride; Demecycline; Denofungin; Diaveridine; Dicloxacillin;    Dicloxacillin Sodium; Dihydrostreptomycin Sulfate; Dipyrithione;    Dirithromycin; Doxycycline; Doxycycline Calcium; Doxycycline    Fosfatex; Doxycycline Hyclate; Droxacin Sodium; Enoxacin; Epicillin;    Epitetracycline Hydrochloride; Erythromycin; Erythromycin Acistrate;    Erythromycin Estolate; Erythromycin Ethylsuccinate; Erythromycin    Gluceptate; Erythromycin Lactobionate; Erythromycin Propionate;    Erythromycin Stearate; Ethambutol Hydrochloride; Ethionamide;    Fleroxacin; Floxacillin; Fludalanine; Flumequine; Fosfomycin;    Fosfomycin Tromethamine; Fumoxicillin; Furazolium Chloride;    Furazolium Tartrate; Fusidate Sodium; Fusidic Acid; Gentamicin    Sulfate; Gloximonam; Gramicidin; Haloprogin; Hetacillin; Hetacillin    Potassium; Hexedine; Ibafloxacin; Imipenem; Isoconazole; Isepamicin;    Isoniazid; Josamycin; Kanamycin Sulfate; Kitasamycin;    Levofuraltadone; Levopropylcillin Potassium; Lexithromycin;    Lincomycin; Lincomycin Hydrochloride; Lomefloxacin; Lomefloxacin    Hydrochloride; Lomefloxacin Mesylate; Loracarbef; Mafenide;    Meclocycline; Meclocycline Sulfosalicylate; Megalomicin Potassium    Phosphate; Mequidox; Meropenem; Methacycline; Methacycline    Hydrochloride; Methenamine; Methenamine Hippurate; Methenamine    Mandelate; Methicillin Sodium; Metioprim; Metronidazole    Hydrochloride; Metronidazole Phosphate; Mezlocillin; Mezlocillin    Sodium; Minocycline; Minocycline Hydrochloride; Mirincamycin    Hydrochloride; Monensin; Monensin Sodium; Nafcillin Sodium;    Nalidixate Sodium; Nalidixic Acid; Natamycin; Nebramycin; Neomycin    Palmitate; Neomycin Sulfate; Neomycin Undecylenate; Netilmicin    Sulfate; Neutramycin; Nifuradene; Nifuraldezone; Nifuratel;    Nifuratrone; Nifurdazil; Nifurimide; Nifurpirinol; Nifurquinazol;    Nifurthiazole; Nitrocycline; Nitrofurantoin; Nitromide; Norfloxacin;    Novobiocin Sodium; Ofloxacin; Ormetoprim; Oxacillin Sodium;    Oximonam; Oximonam Sodium; Oxolinic Acid; Oxytetracycline;    Oxytetracycline Calcium; Oxytetracycline Hydrochloride; Paldimycin;    Parachlorophenol; Paulomycin; Pefloxacin; Pefloxacin Mesylate;    Penamecillin; Penicillin G Benzathine; Penicillin G Potassium;    Penicillin G Procaine; Penicillin G Sodium; Penicillin V; Penicillin    V Benzathine; Penicillin V Hydrabamine; Penicillin V Potassium;    Pentizidone Sodium; Phenyl Aminosalicylate; Piperacillin Sodium;    Pirbenicillin Sodium; Piridicillin Sodium; Pirlimycin Hydrochloride;    Pivampicillin Hydrochloride; Pivampicillin Pamoate; Pivampicillin    Probenate; Polymyxin B Sulfate; Porfiromycin; Propikacin;    Pyrazinamide; Pyrithione Zinc; Quindecamine Acetate; Quinupristin;    Racephenicol; Ramoplanin; Ranimycin; Relomycin; Repromicin;    Rifabutin; Rifametane; Rifamexil; Rifamide; Rifampin; Rifapentine;    Rifaximin; Rolitetracycline; Rolitetracycline Nitrate; Rosaramicin;    Rosaramicin Butyrate; Rosaramicin Propionate; Rosaramicin Sodium    Phosphate; Rosaramicin Stearate; Rosoxacin; Roxarsone;    Roxithromycin; Sancycline; Sanfetrinem Sodium; Sarmoxicillin;    Sarpicillin; Scopafungin; Sisomicin; Sisomicin Sulfate;    Sparfloxacin; Spectinomycin Hydrochloride; Spiramycin; Stallimycin    Hydrochloride; Steffimycin; Streptomycin Sulfate; Streptonicozid;    Sulfabenz; Sulfabenzamide; Sulfacetamide; Sulfacetamide Sodium;    Sulfacytine; Sulfadiazine; Sulfadiazine Sodium; Sulfadoxine;    Sulfalene; Sulfamerazine; Sulfameter; Sulfamethazine;    Sulfamethizole; Sulfamethoxazole; Sulfamonomethoxine; Sulfamoxole;    Sulfanilate Zinc; Sulfanitran; Sulfasalazine; Sulfasomizole;    Sulfathiazole; Sulfazamet; Sulfisoxazole; Sulfisoxazole Acetyl;    Sulfisoxazole Diolamine; Sulfomyxin; Sulopenem; Sultamicillin;    Suncillin Sodium; Talampicillin Hydrochloride; Teicoplanin;    Temafloxacin Hydrochloride; Temocillin; Tetracycline; Tetracycline    Hydrochloride; Tetracycline Phosphate Complex; Tetroxoprim;    Thiamphenicol; Thiphencillin Potassium; Ticarcillin Cresyl Sodium;    Ticarcillin Disodium; Ticarcillin Monosodium; Ticlatone; Tiodonium    Chloride; Tobramycin; Tobrarnycin Sulfate; Tosufloxacin;    Trimethoprim; Trimethoprim Sulfate; Trisulfapyrimidines;    Troleandomycin; Trospectomycin Sulfate; Tyrothricin; Vancomycin;    Vancomycin Hydrochloride; Virginiamycin; Zorbarnycin.-   Anticholelithic: Monoctanoin.-   Anticholelithogenic: Chenodiol; Ursodiol.-   Anticholinergic: Alverinc Citrate; Anisotropine Methylbromide;    Atropine; Atropine Oxide Hydrochloride; Atropine Sulfate;    Belladonna; Benapryzine Hydrochloride; Benzetimide Hydrochloride;    Benzilonium Bromide; Biperiden; Biperiden Hydrochloride; Biperiden    Lactate; Clidinium Bromide; Cyclopentolate Hydrochloride;    Dexetimide; Dicyclomine Hydrochloride; Dihexyverine Hydrochloride;    Domazoline Fumarate; Elantrine; Elucaine; Ethybenztropine;    Eucatropine Hydrochloride; Glycopyrrolate; Heteronium Bromide;    Homatropine Hydrobromide; Homatropine Methylbromide; Hyoscyamine;    Hyoscyamine Hydrobromide; Hyoscyamine Sulfate; Isopropamide Iodide;    Mepenzolate Bromide; Methylatropine Nitrate; Metoquizine; Oxybutynin    Chloride; Parapenzolate Bromide; Pentapiperium Methylsulfate;    Phencarbamide; Poldine Methylsulfate; Proglumide; Propantheline    Bromide; Propenzolate Hydrochloride; Scopolamine Hydrobromide;    Tematropium Methylsulfate; Tiquinamide Hydrochloride; Tofenacin    Hydrochloride; Toquizine; Triampyzine Sulfate; Trihexyphenidyl    Hydrochloride; Tropicamide.-   Anticoagulant: Ancrod; Anticoagulant Citrate Dextrose Solution;    Anticoagulant Citrate Phosphate Dextrose Adenine Solution;    Anticoagulant Citrate Phosphate Dextrose Solution; Anticoagulant    Heparin Solution; Anticoagulant Sodium Citrate Solution; Ardeparin    Sodium; Bivalirudin; Bromindione; Dalteparin Sodium; Desirudin;    Dicumarol; Heparin Calcium; Heparin Sodium; Lyapolate Sodium;    Nafanostat Mesylate; Phenprocoumon; Tinzaparin Sodium; Warfarin    Sodium.-   Anticoccidal: Maduramicin.-   Anticonvulsant: Albutoin; Ameltolide; Atolide; Buramate;    Carbamazepine; Cinromide; Citenamide; Clonazepam; Cyheptamide;    Dezinamide; Dimethadione; Divalproex Sodium; Eterobarb;    Ethosuximide; Ethotoin; Flurazepam Hydrochloride; Fluzinamide;    Fosphenytoin Sodium; Gabapentin; Ilepcimide; Lamotrigine; Magnesium    Sulfate; Mephenytoin; Mephobarbital; Methetoin; Methsuximide;    Milacemide Hydrochloride; Nabazenil; Nafimidone Hydrochloride;    Nitrazepam; Phenacemide; Phenobarbital; Phenobarbital Sodium;    Phensuximide; Phenytoin; Phenytoin Sodium; Primidone; Progabide;    Ralitoline; Remacemide Hydrochloride; Ropizine; Sabeluzole;    Stiripentol; Sulthiame; Thiopental Sodium; Tiletamine Hydrochloride;    Topiramate; Trimethadione; Valproate Sodium; Valproic Acid;    Vigabatrin; Zoniclezole Hydrochloride; Zonisamide.-   Antidepressant: Adatanserin Hydrochloride; Adinazolam; Adinazolam    Mesylate, Alaproclate; Aletamine Hydrochloride; Amedalin    Hydrochloride; Amitriptyline Hydrochloride; Amoxapine; Aptazapine    Maleate; Azaloxan Fumarate; Azepindole; Azipramine Hydrochloride;    Bipenamol Hydrochloride; Bupropion Hydrochloride; Butacetin;    Butriptyline Hydrochloride; Caroxazone; Cartazolate; Ciclazindol;    Cidoxepin Hydrochloride; Cilobamine Mesylate; Clodazon    Hydrochloride; Clomipramine Hydrochloride; Cotinine Fumarate;    Cyclindole; Cypenamine Hydrochloride; Cyprolidol Hydrochloride;    Cyproximide; Daledalin Tosylate; Dapoxetine Hydrochloride; Dazadrol    Maleate; Dazepinil Hydrochloride; Desipramine Hydrochloride;    Dexamisole; Deximafen; Dibenzepin Hydrochloride; Dioxadrol    Hydrochloride; Dothiepin Hydrochloride; Doxepin Hydrochloride;    Duloxetine Hydrochloride; Eclanamine Maleate; Encyprate; Etoperidone    Hydrochloride; Fantridone Hydrochloride; Fehmetozole Hydrochloride;    Fenmetramide; Fezolamine Fumarate; Fluotracen Hydrochloride;    Fluoxetine; Fluoxetine Hydrochloride; Fluparoxan Hydrochloride;    Gamfexine; Guanoxyfen Sulfate; Imafen Hydrochloride; Imiloxan    Hydrochloride; Imipramine Hydrochloride; Indeloxazine Hydrochloride;    Intriptyline Hydrochloride; Iprindole; Isocarboxazid; Ketipramine    Fumarate; Lofepramine Hydrochloride; Lortalamine; Maprotiline;    Maprotiline Hydrochloride; Melitracen Hydrochloride; Milacemide    Hydrochloride; Minaprine Hydrochloride; Mirtazapine; Moclobemide;    Modaline Sulfate; Napactadine Hydrochloride; Naparnezole    Hydrochloride; Nefazodone Hydrochloride; Nisoxetine; Nitrafudam    Hydrochloride; Nomifensine Maleate; Nortriptyline Hydrochloride;    Octriptyline Phosphate; Opipramol Hydrochloride; Oxaprotiline    Hydrochloride; Oxypertine; Paroxetine; Phenelzine Sulfate;    Pirandamine Hydrochloride; Pizotyline; Pridefine Hydrochloride;    Prolintane Hydrochloride; Protriptyline Hydrochloride; Quipazine    Maleate; Rolicyprine; Seproxetine Hydrochloride; Sertraline    Hydrochloride; Sibutramine Hydrochloride; Sulpiride; Suritozole;    Tametraline Hydrochloride; Tampramine Fumarate; Tandamine    Hydrochloride; Thiazesim Hydrochloride; Thozalinone; Tomoxetine    Hydrochloride; Trazodone Hydrochloride; Trebenzomine Hydrochloride;    Trimipramine; Trimipramine Maleate; Venlafaxine Hydrochloride;    Viloxazine Hydrochloride; Zimeldine Hydrochloride; Zometapine.-   Antidiabetic: Acetohexamide; Buformin; Butoxamine Hydrochloride;    Camiglibose; Chlorpropamide; Ciglitazone; Englitazone Sodium;    Etoformin Hydrochloride; Gliamilide; Glibornuride; Glicetanile    Sodium; Gliflumide; Glipizide; Glucagon; Glyburide; Glyhexamide;    Glymidine Sodium; Glyoctamide; Glyparamide; Insulin; Insulin,    Dalanated; Insulin Human; Insulin Human, Isophane; Insulin Human    Zinc; Insulin Human Zinc, Extended; Insulin, Isophane; Insulin    Lispro; Insulin, Neutral; Insulin Zinc; Insulin Zinc, Extended;    Insulin Zinc, Prompt; Linogliride; Linogliride Fumarate; Metformin;    Methyl Palmoxirate; Palmoxirate Sodium; Pioglitazone Hydrochloride;    Pirogliride Tartrate; Proinsulin Human; Seglitide Acetate;    Tolazamide; Tolbutamide; Tolpyrramide; Troglitazone; Zopolrestat.-   Antidiarrheal: Rolgamidine, Diphenoxylate hydrochloride (Lomotil),    Metronidazole (Flagyl), Methylprednisolone (Medrol), Sulfasalazine    (Azulfidine).-   Antidiuretic: Argipressin Tannate; Desmopressin Acetate; Lypressin.-   Antidote: Dimercaprol; Edrophonium Chloride; Fomepizole; Leucovorin    Calcium; Levoleucovorin Calcium; Methylene Blue; Protamine Sulfate.-   Antidyskinetic: Selegiline Hydrochloride.-   Anti-emetic: Alosetron Hydrochloride; Batanopride Hydrochloride;    Bemesetron; Benzquinamide; Chlorpromazine; Chlorpromazine    Hydrochloride; Clebopride; Cyclizine Hydrochloride; Dimenhydrinate;    Diphenidol; Diphenidol Hydrochloride; Diphenidol Pamoate; Dolasetron    Mesylate; Domperidone; Dronabinol; Fludorex; Flumeridone;    Galdansetron Hydrochloride; Granisetron; Granisetron Hydrochloride;    Lurosetron Mesylate; Meclizine Hydrochloride; Metoclopramide    Hydrochloride; Metopimazine; Ondansetron Hydrochloride; Pancopride;    Prochlorperazine; Prochlorperazine Edisylate; Prochlorperazine    Maleate; Promethazine Hydrochloride; Thiethylperazine;    Thiethylperazine Malate; Thiethylperazine Maleate; Trimethobenzamide    Hydrochloride; Zacopride Hydrochloride.-   Anti-epileptic: Felbamate; Loreclezole; Tolgabide.-   Anti-estrogen: Clometherone; Delmadinone Acetate; Nafoxidine    Hydrochloride; Nitromifene Citrate; Raloxifene Hydrochloride;    Tamoxifen Citrate; Toremifene Citrate; Trioxifene Mesylate.-   Antifibrinolytic: Nafamostat Mesylate.-   Antifungal: Acrisorcin; Ambruticin; Amphotericin B; Azaconazole;    Azaserine; Basifungin; Bifonazole; Biphenamine Hydrochloride;    Bispyrithione Magsulfex; Butoconazole Nitrate; Calcium Undecylenate;    Candicidin; Carbol-Fuchsin; Chlordantoin; Ciclopirox; Ciclopirox    Olamine; Cilofungin; Cisconazole; Clotrimazole; Cuprimyxin;    Denofungin; Dipyrithione; Doconazole; Econazole; Econazole Nitrate;    Enilconazole; Ethonam Nitrate; Fenticonazole Nitrate; Filipin;    Fluconazole; Flucytosine; Fungimycin; Griseofulvin; Hamycin;    Isoconazole; Itraconazole; Kalafungin; Ketoconazole; Lomofungin;    Lydimycin; Mepartricin; Miconazole; Miconazole Nitrate; Monensin;    Monensin Sodium; Naftifine Hydrochloride; Neomycin Undecylenate;    Nifuratel; Nifurmerone; Nitralamine Hydrochloride; Nystatin;    Octanoic Acid; Orconazole Nitrate; Oxiconazole Nitrate; Oxifungin    Hydrochloride; Parconazole Hydrochloride; Partricin; Potassium    Iodide; Proclonol; Pyritone Zinc; Pyrrolnitrin; Rutamycin;    Sanguinarium Chloride; Saperconazole; Scopafungin; Selenium Sulfide;    Sinefungin; Sulconazole Nitrate; Terbinafine; Terconazole; Thiram;    Ticlatone; Tioconazole; Tolciclate; Tolindate; Tolnaftate;    Triacetin; Triafungin; Undecylenic Acid; Viridofulvin; Zinc    Undecylenate; Zinoconazole Hydrochloride.-   Antiglaucooma agent: Alprenoxime Hydrochloride; Colforsin;    Dapiprazole Hydrochloride; Dipivefrin Hydrochloride; Naboctate    Hydrochloride; Pilocarpine; Pirnabine.-   Antihemophilic: Antihemophilic Factor.-   Antihemorrhagic: Poliglusam.-   Antihistaminic: Acrivastine; Antazoline Phosphate; Astemizole;    Azatadine Maleate; Barmastine; Bromodiphenhydramine Hydrochloride;    Brompheniramine Maleate; Carbinoxamine Maleate; Cetirizine    Hydrochloride; Chlorpheniramine Maleate; Chlorpheniramine    Polistirex; Cinnarizine; Clemastine; Clemastine Fumarate;    Closiramine Aceturate; Cycliramine Maleate; Cyclizine;    Cyproheptadine Hydrochloride; Dexbrompheniramine Maleate;    Dexchlorpheniramine Maleate; Dimethindene Maleate; Diphenhydramine    Citrate; Diphenhydramine Hydrochloride; Dorastine Hydrochloride;    Doxylamine Succinate; Ebastine; Levocabastine Hydrochloride;    Loratadine; Mianserin Hydrochloride; Noberastine; Orphenadrine    Citrate; Pyrabrom; Pyrilamine Maleate; Pyroxamine Maleate; Rocastine    Hydrochloride; Rotoxamine; Tazifylline Hydrochloride; Temelastine;    Terfenadine; Tripelennamine Citrate; Tripelennamine Hydrochloride,    Triprolidine Hydrochloride; Zolamine Hydrochloride.-   Antihyperlipidemic: Cholestyramine Resin; Clofibrate; Colestipol    Hydrochloride; Crilvastatin; Dalvastatin; Dextrothyroxine Sodium;    Fluvastatin Sodium; Gemfibrozil; Lecimibide; Lovastatin; Niacin;    Pravastatin Sodium; Probucol; Simvastatin; Tiqueside; Xenbucin.-   Antihyperlipoproteinemic: Acifran; Beloxamide; Bezafibrate;    Boxidine; Butoxamine Hydrochloride; Cetaben Sodium; Ciprofibrate;    Gemcadiol; Halofenate; Lifibrate; Meglutol; Nafenopin; Pimetine    Hydrochloride; Theofibrate; Tibric Acid; Treloxinate.-   Antihypertensive: Alfuzosin Hydrochloride; Alipamide; Althiazide;    Amiquinsin Hydrochloride; Amlodipine Besylate; Amlodipine Maleate;    Anaritide Acetate; Atiprosin Maleate; Belfosdil; Bemitradine;    Bendacalol Mesylate; Bendroflumethiazide; Benzthazide; Betaxolol    Hydrochloride; Bethanidine Sulfate; Bevantolol Hydrochloride;    Biclodil Hydrochloride; Bisoprolol; Bisoprolol Fumarate; Bucindolol    Hydrochloride; Bupicomide; Buthiazide; Candoxatril; Candoxatrilat;    Captopril; Carvedilol; Ceronapril; Chlorothiazide Sodium;    Cicletanine; Cilazapril; Clonidine; Clonidine Hydrochloride;    Clopamide; Cyclopenthiazide; Cyclothiazide; Darodipine; Debrisoquin    Sulfate; Delapril Hydrochloride; Diapamide; Diazoxide; Dilevalol    Hydrochloride; Diltiazem Malate; Ditekiren; Doxazosin Mesylate;    Ecadotril; Enalapril Maleate; Enalaprilat; Enalkiren; Endralazine    Mesylate; Epithiazide; Eprosartan; Eprosartan Mesylate; Fenoldoparn    Mesylate; Flavodilol Maleate; Flordipine; Flosequinan; Fosinopril    Sodium; Fosinoprilat; Guanabenz; Guanabenz Acetate; Guanacline    Sulfate; Guanadrel Sulfate; Guancydine; Guanethidine Monosulfate;    Guanethidine Sulfate; Guanfacine Hydrochloride; Guanisoquin Sulfate;    Guanoclor Sulfate; Guanoctine Hydrochloride; Guanoxabenz; Guanoxan    Sulfate; Guanoxyfen Sulfate; Hydralazine Hydrochloride; Hydralazine    Polistirex; Hydroflumethiazide; Indacrinone; Indapamide; Indolapril    Hydrochloride; Indoramin; Indoramin Hydrochloride; Indorenate    Hydrochloride; Lacidipine; Leniquinsin; Levcromakalim; Lisinopril;    Lofexidine Hydrochloride; Losartan Potassium; Losulazine    Hydrochloride; Mebutamate; Mecamylamine Hydrochloride; Medroxalol;    Medroxalol Hydrochloride; Methalthiazide; Methyclothiazide;    Methyldopa; Methyldopate Hydrochloride; Metipranolol; Metolazone;    Metoprolol Fumarate; Metoprolol Succinate; Metyrosine; Minoxidil;    Monatepil Maleate; Muzolimine; Nebivolol; Nitrendipine; Ofornine;    Pargyline Hydrochloride; Pazoxide; Pelanserin Hydrochloride;    Perindopril Erburmine; Phenoxybenzamine Hydrochloride; Pinacidil;    Pivopril; Polythiazide; Prazosin Hydrochloride; Primidolol;    Prizidilol Hydrochloride; Quinapril Hydrochloride; Quinaprilat;    Quinazosin Hydrochloride; Quinelorane Hydrochloride; Quinpirole    Hydrochloride; Quinucliun Bromide; Ramipril; Rauwolfia Serpentina;    Reserpine; Saprisartan Potassium; Saralasin Acetate; Sodium    Nitroprusside; Sulfinalol Hydrochloride; Tasosartan; Teludipine    Hydrochloride; Temocapril Hydrochloride; Terazosin Hydrochloride;    Terlakiren; Tiamenidine; Tiamenidine Hydrochloride; Ticrynafen;    Tinabinol; Tiodazosin; Tipentosin Hydrochloride; Trichlormethiazide;    Trimazosin Hydrochloride; Trimethaphan Carnsylate; Trimoxamine    Hydrochloride; Tripamide; Xipamide; Zankiren Hydrochloride;    Zofenoprilat Arginine.-   Antihypotensive: Ciclafrine Hydrochloride; Midodrine Hydrochloride.-   Anti-infective: Difloxacin Hydrochloride; Lauryl Isoquinolinium    Bromide; Moxalactam Disodium; Ornidazole; Pentisomicin; Sarafloxacin    Hydrochloride; Protease inhibitors of HIV and other retroviruses;    Integrase Inhibitors of HIV and other retroviruses; Cefaclor    (Ceclor); Acyclovir (Zovirax), Norfloxacin (Noroxin); Cefoxitin    (Mefoxin); Cefuroxime axetil (Ceftin); Ciprofloxacin (Cipro).-   Anti-infective, topical: Alcohol; Aminacrine Hydrochloride;    Benzethonium Chloride; Bithionolate Sodium; Bromchlorenone;    Carbamide Peroxide; Cetalkonium Chloride; Cetylpyridinium Chloride;    Chlorhexidine Hydrochloride; Clioquinol; Domiphen Bromide;    Fenticlor; Fludazonium Chloride; Fuchsin, Basic; Furazolidone;    Gentian Violet; Halquinols; Hexachlorophene; Hydrogen Peroxide;    Ichthammol; Imidecyl Iodine; Iodine; Isopropyl Alcohol; Mafenide    Acetate; Meralein Sodium; Mercufenol Chloride; Mercury, Ammoniated;    Methylbenzethonium Chloride; Nitrofurazone; Nitromersol; Octenidine    Hydrochloride; Oxychlorosene; Oxychlorosene Sodium;    Parachlorophenol, Camphorated; Potassium Permanganate;    Povidone-Iodine; Sepazonium Chloride; Silver Nitrate; Sulfadiazine,    Silver; Symclosene; Thimerfonate Sodium; Thirerosal: Troclosene    Potassium.-   Anti-inflammatory: Alclofenac; Alclometasone Dipropionate; Algestone    Acetonide; Alpha Amylase; Amcinafal; Amcinafide; Amfenac Sodium;    Amiprilose Hydrochloride; Anakinra; Anirolac; Anitrazafen; Apazone;    Balsalazide Disodium; Bendazac; Benoxaprofen; Benzydamine    Hydrochloride; Bromelains; Broperamole; Budesonide; Carprofen;    Cicloprofen; Cintazone; Cliprofen; Clobetasol Propionate;    Clobetasone Butyrate; Clopirac; Cloticasone Propionate; Cormethasone    Acetate; Cortodoxone; Deflazacort; Desonide; Desoximetasone;    Dexamethasone Dipropionate; Diclofenac Potassium; Diclofenac Sodium;    Diflorasone Diacetate; Diflumidone Sodium; Diflunisal;    Difluprednate; Diftalone; Dimethyl Sulfoxide; Drocinonide;    Endrysone; Enlimomab; Enolicam Sodium; Epirizole; Etodolac;    Etofenamate; Felbinac; Fenamole; Fenbufen; Fenclofenac; Fenclorac;    Fendosal; Fenpipalone; Fentiazac; Flazalone; Fluazacort; Flufenamic    Acid; Flumizole; Flunisolide Acetate; Flunixin; Flunixin Meglumine;    Fluocortin Butyl; Fluorometholone Acetate; Fluquazone; Flurbiprofen;    Fluretofen; Fluticasone Propionate; Furaprofen; Furobufen;    Halcinonide; Halobetasol Propionate; Halopredone Acetate; Ibufenac;    Ibuprofen; Ibuprofen Aluminum; Ibuprofen Piconol; Ilonidap;    Indomethacin; Indomethacin Sodium; Indoprofen; Indoxole; Intrazole;    Isoflupredone Acetate; Isoxepac; Isoxicam; Ketoprofel; Lofemizole    Hydrochloride; Lornoxicam; Loteprednol Etabonate; Meclofenamate    Sodium; Meclofenamic Acid; Meclorisone Dibutyrate; Mefenamic Acid;    Mesalamine; Meseclazone; Methylprednisolone Suleptanate;    Morniflumate; Nabumetone; Naproxen; Naproxen Sodium; Naproxol;    Nimazone; Olsalazine Sodium; Orgotein; Orpanoxin; Oxaprozin;    Oxyphenbutazone; Paranyline Hydrochloride; Pentosan Polysulfate    Sodium; Phenbutazone Sodium Glycerate; Pirfenidone; Piroxicam;    Piroxicam Cinnamate; Piroxicam Olamine; Pirprofen; Prednazate;    Prifelone; Prodolic Acid; Proquazone; Proxazole; Proxazole Citrate;    Rimexolone; Romazarit; Salcolex; Salnacedin; Salsalate; Sanguinarium    Chloride; Seclazone; Sermetacin; Sudoxicam; Sulindac; Suprofen;    Talmetacin; Talniflumate; Talosalate; Tebufelone; Tenidap; Tenidap    Sodium; Tenoxicam; Tesicam; Tesimide; Tetrydamine; Tiopinac;    Tixocortol Pivalate; Tolmetin; Tolmetin Sodium; Triclonide;    Triflumidate; Zidometacin; Zomepirac Sodium.-   Antikeratinizing agent: Doretinel; Linarotene; Pelretin.-   Antimalarial: Acedapsone; Amodiaquine Hydrochloride; Amquinate;    Arteflene; Chloroquine; Chloroquine Hydrochloride; Chloroquine    Phosphate; Cycloguanil Pamoate; Enpiroline Phosphate; Halofantrine    Hydrochloride; Hydroxychloroquine Sulfate; Mefloquine Hydrochloride;    Menoctone; Mirincamycin Hydrochloride; Primaquine Phosphate;    Pyrimethamine; Quinine Sulfate; Tebuquine.-   Antimicrobial: Aztreonam; Chlorhexidine Gluconate; Imidurea;    Lycetamine; Nibroxane; Pirazmonam Sodium; Propionic Acid; Pyrithione    Sodium; Sanguinarium Chloride; Tigemonam Dicholine.-   Antimigraine: Dolasetron Mesylate; Naratriptan Hydrochloride;    Sergolexole Maleate; Sumatriptan Succinate; Zatosetron Maleate.-   Antimitotic: Podofilox.-   Antimycotic: Amorolfine.-   Antinauseant: Buclizine Hydrochloride; Cyclizine Lactate; Naboctate    Hydrochloride.-   Antineoplastic: Acivicin; Aclarubicin; Acodazole Hydrochloride;    Acronine; Adozelesin; Aldesleukin; Altretamine; Ambomycin;    Ametantrone Acetate; Aminoglutethimide; Amsacrine; Anastrozole;    Anthramycin;Asparaginase; Asperlin; Azacitidine; Azetepa;    Azotomycin; Batimastat; Benzodepa; Bicalutamide; Bisantrene    Hydrochloride; Bisnafide Dimesylate; Bizelesin; Bleomycin Sulfate;    Brequinar Sodium; Bropirimine; Busulfan; Cactinomycin; Calusterone;    Caracemide; Carbetimer; Carboplatin; Carmustine; Carubicin    Hydrochloride; Carzelesin; Cedefingol; Clorambucil; Cirolemycin;    Cisplatin; Cladribine; Crisnatol Mesylate; Cyclophosphamide;    Cytarabine; Dacarbazine; Dactinomycin; Daunorubicin Hydrochloride;    Decitabine; Dexormaplatin; Dezaguanine; Dezaguanine Mesylate;    Diaziquone; Docetaxel; Doxorubicin; Doxorubicin Hydrochloride;    Droloxifene; Droloxifene Citrate; Dromostanolone Propionate;    Duazomycin; Edatrexate; Eflornithine Hydrochloride; Elsamitrucin;    Enloplatin; Enpromate; Epipropidine; Epirubicin Hydrochloride;    Erbulozole; Esorubicin Hydrochloride; Estramustine; Estramustine    Phosphate Sodium; Etanidazole; Ethiodized Oil I 131; Etoposide;    Etoposide Phosphate; Etoprine; Fadrozole Hydrochloride; Fazarabine;    Fenretinide; Floxuridine; Fludarabine Phosphate; Fluorouracil;    Flurocitabine; Fosquidone; Fostriecin Sodium; Gemcitabine;    Gemcitabine Hydrochloride; Gold Au 198; Hydroxyurea; Idarubicin    Hydrochloride; Ifosfamide; Ilmofosine; Interferon Alfa-2a;    Interferon Alfa-2b; Interferon Alfa-n1; Interferon Alfa-n3;    Interferon Beta-Ia; Interferon Gamma-Ib; Iproplatin; Irinotecan    Hydrochloride; Lanreotide Acetate; Letrozole; Leuprolide Acetate;    Liarozole Hydrochloride; Lometrexol Sodium; Lomustine; Losoxantrone    Hydrochloride; Masoprocol; Maytansine; Mechlorethamine    Hydrochloride; Megestrol Acetate; Melengestrol Acetate; Melphalan;    Menogaril; Mercaptopurine; Methotrexate; Methotrexate Sodium;    Metoprine; Meturedepa; Mitindomide; Mitocarcin; Mitocromin;    Mitogillin; Mitomalcin; Mitomycin; Mitosper; Mitotane; Mitoxantrone    Hydrochloride; Mycophenolic Acid; Nocodazole; Nogalamycin;    Ormaplatin; Oxisuran; Paclitaxel; Pegaspargase; Peliomycin;    Pentamustine; Peplomycin Sulfate; Perfosfamide; Pipobroman;    Piposulfan; Piroxantrone Hydrochloride; Plicamycin; Plomestane;    Porfimer Sodium; Porfiromycin; Prednimustine; Procarbazine    Hydrochloride; Puromycin; Puromycin Hydrochloride; Pyrazofurin;    Riboprine; Rogletimide; Safingol; Safingol Hydrochloride; Semustine;    Simtrazene; Sparfosate Sodium; Sparsomycin; Spirogermanium    Hydrochloride; Spiromustine; Spiroplatin; Streptonigrin;    Streptozocin; Strontium Chloride Sr 89; Sulofenur; Talisomycin;    Taxane; Taxoid; Tecogalan Sodium; Tegafur; Teloxantrone    Hydrochloride; Temoporfin; Teniposide; Teroxirone; Testolactone;    Thiamiprine; Thioguanine; Thiotepa; Tiazofurin; Tirapazamine;    Topotecan Hydrochloride; Toremifene Citrate; Trestolone Acetate;    Triciribine Phosphate; Trimetrexate; Trimetrexate Glucuronate;    Triptorelin; Tubulozole Hydrochloride; Uracil Mustard; Uredepa;    Vapreotide; Verteporfin; Vinblastine Sulfate; Vincristine Sulfate;    Vindesine; Vindesine Sulfate; Vinepidine Sulfate; Vinglycinate    Sulfate; Vinleurosine Sulfate; Vinorelbine Tartrate; Vinrosidine    Sulfate; Vinzolidine Sulfate; Vorozole; Zeniplatin; Zinostatin;    Zorubicin Hydrochloride.-   Other anti-neoplastic compounds include: 20-epi-1,25    dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; aclarubicin;    acylfulvene; adecypenol; adozelesin; aldesleukin; ALL-TK    antagonists; altretamine; ambamustine; amidox; amifostine;    aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole;    andrographolide; angiogenesis inhibitors; antagonist D; antagonist    G; antarelix; anti-dorsalizing morphogenetic protein-1;    antiandrogen, prostatic carcinoma; antiestrogen; antineoplaston;    antisense oligonucleotides; aphidicolin glycinate; apoptosis gene    modulators; apoptosis regulators; apurinic acid; ara-CDP-DL-PTBA;    arginine deaminase; asulacrine; atamestane; atrimustine; axinastatin    1; axinastatin 2; axinastatin 3; azasetron; azatoxin; azatyrosine;    baccatin III derivatives; balanol; batimastat; BCR/ABL antagonists;    benzochlorins; benzoylstaurosporine; beta lactam derivatives;    beta-alethine; betaclamycin B; betulinic acid; bFGF inhibitor;    bicalutamide; bisantrene; bisaziridinylspermine; bisnafide;    bistratene A; bizelesin; breflate; bropirimine; budotitane;    buthionine sulfoximine; calcipotriol; calphostin C; camptothecin    derivatives; canarypox IL-2; capecitabine;    carboxamide-amino-triazole; carboxyamidotriazole; CaRest M3; CARN    700; cartilage derived inhibitor; carzelesin; casein kinase    inhibitors (ICOS); castanospermine; cecropin B; cetrorelix;    chlorins; chloroquinoxaline sulfonamide; cicaprost; cis-porphyrin;    cladribine; clornifene analogues; clotrimazole; collismycin A;    collismycin B; combretastatin A4; combretastatin analogue;    conagenin; crambescidin 816; crisnatol; cryptophycin 8; cryptophycin    A derivatives; curacin A; cyclopentanthraquinones; cycloplatam;    cypemycin; cytarabine ocfosfate; cytolytic factor; cytostatin;    dacliximab; decitabine; dehydrodidemnin B; deslorelin;    dexifosfamide; dexrazoxane; dexverapamil; diaziquone; didemnin B;    didox; diethylnorspermine; dihydro-5-azacytidine; dihydrotaxol, 9-;    dioxamycin; diphenyl spiromustine; docosanol; dolasetron;    doxifluridine; droloxifene; dronabinol; duocarmycin SA; ebselen;    ecomustine; edelfosine; edrecolomab; eflornithine; elemene;    emitefur; epirubicin; epristeride; estramustine analogue; estrogen    agonists; estrogen antagonists; etanidazole; etoposide phosphate;    exemestane; fadrozole; fazarabine; fenretinide; filgrastim;    finasteride; flavopiridol; flezelastine; fluasterone; fludarabine;    fluorodaunorunicin hydrochloride; forfenimex; formestane;    fostriecin; fotemustine; gadolinium texaphyrin; gallium nitrate;    galocitabine; ganirelix; gelatinase inhibitors; gemcitabine;    glutathione inhibitors; hepsulfam; heregulin; hexamethylene    bisacetamide; hypericin; ibandronic acid; idarubicin; idoxifene;    idramantone; ilmofosine; ilomastat; imidazoacridones; imiquimod;    immunostimulant peptides; insulin-like growth factor-1 receptor    inhibitor; interferon agonists, interferons; interleukins;    iobenguane; iododoxoribicin; ipomeanol, 4-; irinotecan; iroplact;    irsogladine; isobengazole; isohomohalicondrin B; itasetron;    jasplakinolide; kahalalide F; lamellarin-N triacetate; lanreotide;    leinamycin; lenograstim; lentinan sulfate; leptolstatin; letrozole;    leukemia inhibiting factor; leukocyte alpha interferon;    leuprolide+estrogen+progesterone; leuprorelin; levamisole;    liarozole; linear polyamine analogue; lipophilic disaccharide    peptide; lipophilic platinum compounds; lissoclinamide 7;    lobaplatin; lombricine; lometrexol; lonidamine; losoxantrone;    lovastatin; loxoribine; lurtotecan; lutetium texaphyrin;    lysofylline; lytic peptides; maitansine; mannostatin A; marimastat;    masoprocol; maspin; matrilysin inhibitors; matrix metalloproteinase    inhibitors; menogaril; merbarone; meterelin; methioninase;    metoclopramide; MIF inhibitor; mifepristone; miltefosine;    mirimostim; mismatched double stranded RNA; mitoguazone; mitolactol;    mitomycin analogues; mitonafide; mitotoxin fibroblast growth    factor-saporin; mitoxantrone; mofarotene; molgramostim; monoclonal    antibody, human chorionic gonadotrophin; monophosphoryl lipid    A+myobacterium cell wall sk; mopidamol; multiple drug resistance    gene inhibitor; multiple tumor suppressor 1-based therapy; mustard    anticancer agent; mycaperoxide B; mycobacterial cell wall extract;    myriaporone; N-acetyldinaline; N-substituted benzamides; nafarelin;    nagrestip; naloxone+pentazocine; napavin; naphterpin; nartograstim;    nedaplatin; nemorubicin; neridronic acid; neutral endopeptidase;    nilutamide; nisamycin; nitric oxide modulators; nitroxide    antioxidant; nitrullyn; O6-benzylguanine; octreotide; okicenone;    oligonucleotides; onapristone; ondansetron; ondansetron; oracin;    oral cytokine inducer; ormaplatin; osaterone; oxaliplatin;    oxaunomycin; paclitaxel analogues; paclitaxel derivatives;    palauamine; palmitoylrhizoxin; pamidronic acid; panaxytriol;    panomifene; parabactin; pazelliptine; pegaspargase; peldesine;    pentosan polysulfate sodium; pentostatin; pentrozole; perflubron;    perfosfamide; perillyl alcohol; phenazinomycin; phenylacetate;    phosphatase inhibitors; picibanil; pilocarpine hydrochloride;    pirarubicin; piritrexim; placetin A; placetin B; plasminogen    activator inhibitor; platinum complex; platinum compounds;    platinum-triamine complex; porfimer sodium; porfiromycin; propyl    bis-acridone; prostaglandin J2; proteasome inhibitors; protein    A-based immune modulator; protein kinase C inhibitor; protein kinase    C inhibitors, microalgal; protein tyrosine phosphatase inhibitors;    purine nucleoside phosphorylase inhibitors; purpurins;    pyrazoloacridine; pyridoxylated hemoglobin polyoxyethylene    conjugate; raf antagonists; raltitrexed; ramosetron; ras farnesyl    protein transferase inhibitors; ras inhibitors; ras-GAP inhibitor;    retelliptine demethylated; rhenium Re 186 etidronate; rhizoxin;    ribozymes; RII retinamide; rogletimide; rohitukine; romurtide;    roquinimex; rubiginone B1; ruboxyl; safingol; saintopin; SarCNU;    sarcophytol A; sargramostim; Sdi 1 mimetics; semustine; senescence    derived inhibitor 1; sense oligonucleotides; signal transduction    inhibitors; signal transduction modulators; single chain antigen    binding protein; sizofiran; sobuzoxane; sodium borocaptate; sodium    phenylacetate; solverol; somatomedin binding protein; sonermin;    sparfosic acid; spicamycin D; spiromustine; splenopentin;    spongistatin 1; squalamine; stem cell inhibitor; stem-cell division    inhibitors; stipiamide; stromelysin inhibitors; sulfinosine;    superactive vasoactive intestinal peptide antagonist; suradista;    suramin; swainsonine; synthetic glycosaminoglycans; tallimustine;    tamoxifen methiodide; tauromustine; tazarotene; tecogalan sodium;    tegafur; tellurapyrylium; telomerase inhibitors; temoporfin;    temozolomide; teniposide; tetrachlorodecaoxide; tetrazomine;    thaliblastine; thalidomide; thiocoraline; thrombopoietin;    thrombopoietin mimetic; thymalfasin; thymopoietin receptor agonist;    thymotrinan; thyroid stimulating hormone; tin ethyl etiopurpurin;    tirapazamine; titanocene dichloride; topotecan;    topsentin;toremifene; totipotent stem cell factor; translation    inhibitors; tretinoin; triacetyluridine; triciribine; trimetrexate;    triptorelin; tropisetron; turosteride; tyrosine kinase inhibitors;    tyrphostins; UBC inhibitors; ubenimex; urogenital sinus-derived    growth inhibitory factor; urokinase receptor antagonists;    vapreotide; variolin B; vector system, erythrocyte gene therapy;    velaresol; veramine; verdins; verteporfin; vinorelbine; vinxaltine;    vitaxin; vorozole; zanoterone; zeniplatin; zilascorb; zinostatin    stimalamer.

Anti-cancer Supplementary Potentiating Agents: Tricyclic anti-depressantdrugs (e.g., imipramine, desipramine, amitryptyline, clomipramine,trimipramine, doxepin, nortriptyline, protriptyline, anoxapine andmaprotiline); non-tricyclic anti-depressant drugs (e.g., sertraline,trazodone and citalopram); Ca⁺⁺ antagonists (e.g., verapamil,nifedipine, nitrendipine and caroverine); Calmodulin inhibitors (e.g.,prenylamine, trifluoroperazine and clomipramine); Amphotericin B;Triparanol analogues (e.g., tamoxifen); antiarrhyhmic drugs (e.g.,quinidine); anitihypertensive drugs (e.g., reserpine); Thiol depleters(e.g., buthionine and sulfoximine) and Multiple Drug Resistance reducingagents such as Cremaphor EL. The compounds of the invention also can beadministered with cytokines such as granulocyte colony stimulatingfactor.

-   Antineutropenic: Filgrastim; Lenograstim; Molgramostim; Regramostim;    Sargramostim.-   Antiobsessional agent: Fluvoxamine Maleate.-   Antiparasitic: Abamectin; Clorsulon; Ivermectin.-   Antiparkinsonian: Benztropine Mesylate; Biperiden; Biperiden    Hydrochloride; Biperiden Lactate; Carmantadine; Ciladopa    Hydrochloride; Dopamantine; Ethopropazine Hydrochloride; Lazabemide;    Levodopa; Lometraline Hydrochloride; Mofegiline Hydrochloride;    Naxagolide Hydrochloride; Pareptide Sulfate; Procyclidine    Hydrochloride; Quinelorane Hydrochloride; Ropinirole Hydrochloride;    Selegiline Hydrochloride; Tolcapone; Trihexyphenidyl Hydrochloride.-   Antiperistaltic: Difenoximide Hydrochloride; Difenoxin;    Diphenoxylate Hydrochloride; Fluperamide; Lidamidine Hydrochloride;    Loperamide Hydrochloride; Malethamer; Nufenoxole; Paregoric.-   Antipneumocystic: Atovaquone.-   Antiproliferative agent: Piritrexim Isethionate.-   Antiprostatic hypertrophy: Sitogluside.-   Antiprotozoal: Amodiaquine; Azanidazole; Bamnidazole; Carnidazole;    Chlortetracycline Bisulfate; Chlortetracycline Hydrochloride;    Flubendazole; Flunidazole; Halofuginone Hydrobromide; Imidocarb    Hydrochloride; Ipronidazole; Metronidazole; Misonidazole;    Moxnidazole; Nitarsone; Partricin; Puromycin; Puromycin    Hydrochloride; Ronidazole; Sulnidazole; Tinidazole.-   Antipruritic: Cyproheptadine Hydrochloride; Methdilazine;    Methdilazine Hydrochloride; Trimeprazine Tartrate.-   Antipsoriatic: Acitretin; Anthralin; Azaribine; Calcipotriene;    Cycloheximide; Enazadrem Phosphate; Etretinate; Liarozole Fumarate;    Lonapalene; Tepoxalin.-   Antipsychotic: Acetophenazine Maleate; Alentemol Hydrobromide;    Alpertine; Azaperone; Batelapine Maleate; Benperidol; Benzindopyrine    Hydrochloride; Brofoxine; Bromperidol; Bromperidol Decanoate;    Butaclamol Hydrochloride; Butaperazine; Butaperazine Maleate;    Carphenazine Maleate; Carvotroline Hydrochloride; Chlorpromazine;    Chlorpromazine Hydrochloride; Chlorprothixene; Cinperene;    Cintriamide; Clomacran Phosphate; Clopenthixol; Clopimozide;    Clopipazan Mesylate; Cloroperone Hydrochloride; Clothiapine;    Clothixamide Maleate; Clozapine; Cyclophenazine Hydrochloride;    Droperidol; Etazolate Hydrochloride; Fenimide; Flucindole;    Flunezapine; Fluphenazine Decanoate; Fluphenazine Enanthate;    Fluphenazine Hydrochloride; Fluspiperone; Fluspirilene; Flutroline;    Gevotroline Hydrochloride; Halopemide; Haloperidol; Haloperidol    Decanoate; Iloperidone; Imidoline Hydrochloride; Lenperone;    Mazapertine Succinate; Mesoridazine; Mesoridazine Besylate;    Metiapine; Milenperone; Milipertine; Molindone Hydrochloride;    Naranol Hydrochloride; Neflumozide Hydrochloride; Ocapridone;    Olanzapine; Oxiperomide; Penfluridol; Pentiapine Maleate;    Perphenazine; Pimozide; Pinoxepin Hydrochloride; Pipamperone;    Piperacetazine; Pipotiazine Palmitate; Piquindone Hydrochloride;    Prochlorperazine Edisylate; Prochlorperazine Maleate; Promazine    Hydrochloride; Remoxipride; Remoxipride Hydrochloride; Rimcazole    Hydrochloride; Seperidol Hydrochloride; Sertindole; Setoperone;    Spiperone; Thioridazine; Thioridazine Hydrochloride; Thiothixene;    Thiothixene Hydrochloride; Tioperidone Hydrochloride; Tiospirone    Hydrochloride; Trifluoperazine Hydrochloride; Triflupridol;    Triflupromazine; Triflupromazine Hydrochloride; Ziprasidone    Hydrochloride.-   Antirheumatic: Auranofin; Aurothioglucose; Bindarit; Lobenzarit    Sodium; Phenylbutazone; Pirazolac; Prinomide Tromethamine;    Seprilose.-   Antischistosomal: Becanthone Hydrochloride; Hycanthone; Lucanthone    Hydrochloride; Niridazole; Oxamniquine; Pararosaniline Pamoate;    Teroxalene Hydrochloride.-   Antiseborrheic: Chloroxine; Piroctone; Piroctone Olamine; Resorcinol    Monoacetate.-   Antisecretory: Arbaprostil; Deprostil; Fenoctimine Sulfate;    Octreotide, Octreotide Acetate; Omeprazole Sodium; Rioprostil;    Trimoprostil.-   Antispasmodic: Stilonium Iodide; Tizanidine Hydrochloride.-   Antithrombotic: Anagrelide Hydrochloride; Bivalirudin; Dalteparin    Sodium; Danaparoid Sodium; Dazoxiben Hydrochloride; Efegatran    Sulfate; Enoxaparin Sodium; Ifetroban; Ifetroban Sodium; Tinzaparin    Sodium; Trifenagrel.-   Antitussive: Benzonatate; Butamirate Citrate; Chlophedianol    Hydrochloride; Codeine Polistirex; Codoxime; Dextromethorphan;    Dextromethorphan Hydrobromide; Dextromethorphan Polistirex; Ethyl    Dibunate; Guaiapate; Hydrocodone Bitartrate; Hydrocodone Polistirex;    Levopropoxyphene Napsylate; Noscapine; Pemerid Nitrate; Pipazethate;    Suxemerid Sulfate.-   Anti-ulcerative: Aceglutamide Aluminum; Cadexomer Iodine; Cetraxate    Hydrochloride; Enisoprost; Isotiquimide; Lansoprazole; Lavoltidine    Succinate; Misoprostol; Nizatidine; Nolinium Bromide; Pantoprazole;    Pifarnine; Pirenzepine Hydrochloride; Rabeprazole Sodium;    Remiprostol; Roxatidine Acetate Hydrochloride; Sucralfate;    Sucrosofate Potassium; Tolimidone.-   Anti-urolithic: Cysteamine; Cysteamine Hydrochloride; Tricitrates.-   Antiviral: Acemannan; Acyclovir; Acyclovir Sodium; Adefovir;    Alovudine; Alvircept Sudotox; Amantadine Hydrochloride; Aranotin;    Arildone; Atevirdine Mesylate; Avridine; Cidofovir; Cipamfylline;    Cytarabine Hydrochloride; Delavirdine Mesylate; Desciclovir;    Didanosine; Disoxaril; Edoxudine; Enviradene; Enviroxime;    Famciclovir; Farnotine Hydrochloride; Fiacitabine; Fialuridine;    Fosarilate; Foscarnet Sodium; Fosfonet Sodium; Ganciclovir;    Ganciclovir Sodium; Idoxuridine; Kethoxal; Lamivudine; Lobucavir;    Memotine Hydrochloride; Methisazone; Nevirapine; Penciclovir;    Pirodavir; Ribavirin; Rimantadine Hydrochloride; Saquinavir    Mesylate; Somantadine Hydrochloride; Sorivudine; Statolon;    Stavudine; Tilorone Hydrochloride; Trifluridine; Valacyclovir    Hydrochloride; Vidarabine; Vidarabine Phosphate; Vidarabine Sodium    Phosphate; Viroxime; Zalcitabine; Zidovudine; Zinviroxime.-   Appetite suppressant: Dexfenfluramine Hydrochloride; Phendimetrazine    Tartrate; Phentermine Hydrochloride.-   Benign prostatic hyperplasia therapy agent: Tamsulosin    Hydrochloride.-   Blood glucose regulators: Human insulin; Glucagon; Tolazamide;    Tolbutamide; Chloropropamide; Acetohexamide and Glipizide.-   Bone resorption inhibitor: Alendronate Sodium; Etidronate Disodium;    Pamidronate Disodium.-   Bronchodilator: Albuterol; Albuterol Sulfate; Azanator Maleate;    Bamifylline Hydrochloride; Bitolterol Mesylate; Butaprost;    Carbuterol Hydrochloride; Clorprenaline Hydrochloride; Colterol    Mesylate; Doxaprost; Doxofylline; Dyphylline; Enprofylline;    Ephedrine; Ephedrine Hydrochloride; Fenoterol; Fenprinast    Hydrochloride; Guaithylline; Hexoprenaline Sulfate; Hoquizil    Hydrochloride; Ipratropium Bromide; Isoetharine; Isoetharine    Hydrochloride; Isoetharine Mesylate; Isoproterenol Hydrochloride;    Isoproterenol Sulfate; Metaproterenol Polistirex; Metaproterenol    Sulfate; Nisbuterol Mesylate; Oxtriphylline; Picumeterol Fumarate;    Piquizil Hydrochloride; Pirbuterol Acetate; Pirbuterol    Hydrochloride; Procaterol Hydrochloride; Pseudoephedrine Sulfate;    Quazodine; Quinterenol Sulfate; Racepinephrine; Racepinephrine    Hydrochloride; Reproterol Hydrochloride; Rimiterol Hydrobromide;    Salmeterol; Salmeterol Xinafoate; Soterenol Hydrochloride;    Sulfonterol Hydrochloride; Suloxifen Oxalate; Terbutaline Sulfate;    Theophylline; Xanoxate Sodium; Zindotrine; Zinterol Hydrochloride.-   Carbonic anhydrase inhibitor: Acetazolamide; Acetazolamide Sodium,    Dichlorphenamide; Dorzolamide Hydrochloride; Methazolamide;    Sezolamide Hydrochloride.-   Cardiac depressant: Acecainide Hydrochloride; Acetylcholine    Chloride; Actisomide; Adenosine; Amiodarone; Aprindine; Aprindine    Hydrochloride; Artilide Fumarate; Azimilide Dihydrochloride;    Bidisomide; Bucainide Maleate; Bucromarone; Butoprozine    Hydrochloride; Capobenate Sodium; Capobenic Acid; Cifenline;    Cifenline Succinate; Clofilium Phosphate; Disobutamide;    Disopyramide; Disopyramide Phosphate; Dofetilide; Drobuline;    Edifolone Acetate; Emilium Tosylate; Encainide Hydrochloride;    Flecainide Acetate; Ibutilide Fumarate; Indecainide Hydrochloride;    Ipazilide Fumarate; Lorajmine Hydrochloride; Lorcainide    Hydrochloride; Meobentine Sulfate; Mexiletine Hydrochloride;    Modecainide; Moricizine; Oxiramide; Pirmenol Hydrochloride;    Pirolazamide; Pranolium Chloride; Procainamide Hydrochloride;    Propafenone Hydrochloride; Pyrinoline; Quindonium Bromide; Quinidine    Gluconate; Quinidine Sulfate; Recainam Hydrochloride; Recainam    Tosylate; Risotilide Hydrochloride; Ropitoin Hydrochloride;    Sematilide Hydrochloride; Suricainide Maleate; Tocainide; Tocainide    Hydrochloride; Transcainide.-   Cardioprotectant: Dexrazoxane; Draflazine.-   Cardiotonic: Actodigin; Amrinone; Bemoradan; Butopamine; Carbazeran;    Carsatrin Succinate; Deslanoside; Digitalis; Digitoxin; Digoxin;    Dobutamine; Dobutamine Hydrochloride; Dobutamine Lactobionate;    Dobutamine Tartrate; Enoximone; Imazodan Hydrochloride; Indolidan;    Isomazole Hydrochloride; Levdobutamine Lactobionate; Lixazinone    Sulfate; Medorinone; Milrinone; Pelrinone Hydrochloride; Pimobendan;    Piroximone; Prinoxodan; Proscillaridin; Quazinone; Tazolol    Hydrochloride; Vesnarinone.-   Cardiovascular agent: Dopexamine; Dopexamine Hydrochloride.-   Choleretic: Dehydrocholic Acid; Fencibutirol; Hymecromone;    Piprozolin; Sincalide; Tocamphyl.-   Cholinergic: Aceclidine; Bethanechol Chloride; Carbachol; Demecarium    Bromide; Dexpanthenol; Echothiophate Iodide; Isoflurophate;    Methacholine Chloride; Neostigmine Bromide; Neostigmine    Methylsulfate; Physostigmine; Physostigmine Salicylate;    Physostigmine Sulfate; Pilocarpine; Pilocarpine Hydrochloride;    Pilocarpine Nitrate; Pyridostignine Bromide.-   Cholinergic agonist: Xanomeline; Xanomeline Tartrate.-   Cholinesterase Deactivator: Obidoxime Chloride; Pralidoxime    Chloride; Pralidoxime Iodide; Pralidoxime Mesylate.-   Coccidiostat: Arprinocid; Narasin; Semduramicin; Semduramicin    Sodium.-   Cognition adjuvant: Ergoloid Mesylates; Piracetam; Pramiracetam    Hydrochloride; Pramiracetam Sulfate; Tacrine Hydrochloride.-   Cognition enhancer: Besipirdine Hydrochloride; Linopirdine;    Sibopirdine.-   Depressant: Omeprazole.-   Diagnostic aid: Aminohippurate Sodium; Anazolene Sodium; Arclofenin;    Arginine; Bentiromide; Benzylpenicilloyl Polylysine; Butedronate    Tetrasodiun; Butilfenin; Coccidioidin; Corticorelin Ovine    Triflutate; Corticotropin, Repository; Corticotropin Zinc Hydroxide;    Diatrizoate Meglumine; Diatrizoate Sodium; Diatrizoic Acid;    Diphtheria Toxin for Schick Test; Disofenin; Edrophonium Chloride;    Ethiodized Oil; Etifenin; Exametazime; Ferristenc; Ferumoxides;    Ferumoxsil; Fluorescein; Fluorescein Sodium; Gadobenate Dimeglumine;    Gadoteridol; Gadodiamide; Gadopentetate Dimegiumine;    Gadoversetamide; Histoplasmin; Impromidine Hydrochloride;    Indigotindisulfonate Sodium; Indocyanine Green; Iobenguane Sulfate I    123; Iobenzamic Acid; Iocarmate Meglumine; Iocarmic Acid; Iocetamic    Acid; Iodamide; Iodamide Megiumine; Iodipamide Meglumine; Iodixanol;    Iodoxamate Meglumine; Iodoxamic Acid; Ioglicic Acid; Ioglucol;    Ioglucomide; Ioglycamic Acid; Iogulamide; Iohexol; Iomeprol;    Iopamidol; Iopanoic Acid; Iopentol; Iophendylate; Iprofenin;    Iopronic Acid; Ioprocemic Acid; Iopydol; Iopydone; Iosefamic Acid;    Ioseric Acid; Iosulamide Meglumine; Iosumetic Acid; Iotasul;    Iotetric Acid; Iothalamate Meglumine; Iothalamate Sodium; Iothalamic    Acid; Iotrolan; Iotroxic Acid; Ioversol; Ioxaglate Meglumine;    Ioxagiate Sodium; Ioxaglic Acid; Ioxilan; Ioxotrizoic Acid; Ipodate    Calcium; Ipodate Sodium; Isosulfan Blue; Leukocyte Typing Serum;    Lidofenin; Mebrofenin; Meglumine; Metrizamide; Metrizoate Sodium;    Metyrapone; Metyrapone Tartrate; Mumps Skin Test Antigen; Pentetic    Acid; Propyliodone; Quinaldine Blue; Schick Test Control; Sermorelin    Acetate; Sodium Iodide I 123; Sprodiamide; Stannous Pyrophosphate;    Stannous Sulfur Colloid; Succimer; Teriparatide Acetate;    Tetrofosmin; Tolbutamide Sodium; Tuberculin; Tyropanoate Sodium;    Xylose.-   Diuretic: Ambuphylline; Ambuside; Amiloride Hydrochloride;    Azolimine; Azosemide; Brocrinat; Bumetanide; Chlorothiazide;    Chlorthalidone; Clazolimine; Clorexolone; Ethacrynate Sodium;    Ethacrynic Acid; Etozolin; Fenquizone; Furosemide;    Hydrochlorothiazide; Isosorbide; Mannitol; Mefruside; Ozolinone;    Piretanide; Spiroxasone; Torsemide; Triamterene; Triflocin; Urea.-   Doparninergic agent: Ibopamine.-   Ectoparasiticide: Nifluridide; Permethrin.-   Emetic: Apomorphine Hydrochloride.-   Enzyme inhibitor: Acetohydroxamic Acid; Alrestatin Sodium;    Aprotinin; Benazepril Hydrochloride; Benazeprilat; Benurestat;    Bromocriptine; Bromocriptine Mesylate; Cilastatin Sodium;    Flurofamide; Lergotrile; Lergotrile Mesylate; Levcycloserine;    Libenzapril; Pentopril; Pepstatin; Perindopril; Polignate Sodium;    Sodium Amylosulfate; Sorbinil; Spirapril Hydrochloride; Spiraprilat;    Taleranol; Teprotide; Tolfamide; Zofenopril Calcium.-   Estrogen: Chlorotrianisene; Dienestrol; Diethylstilbestrol;    Diethylstilbestrol Diphosphate; Equilin; Estradiol; Estradiol    Cypionate; Estradiol Enanthate; Estradiol Undecylate; Estradiol    Valerate; Estrazinol Hydrobromide; Estriol; Estrofurate; Estrogens,    Conjugated; Estrogens, Esterified; Estrone; Estropipate; Ethinyl    Estradiol; Fenestrel; Mestranol; Nylestriol; Quinestrol.-   Fibrinolytic: Anistreplase; Bisobrin Lactate; Brinolase.-   Free oxygen radical scavenger: Pegorgotein.-   Gastrointestinal Motility agents: Cisapride (Propulsid);    Metoclopramide (Reglan); Hyoscyamine (Levsin).-   Glucocorticoid: Amcinonide; Beclomethasone Dipropionate;    Betamethasone; Betamethasone Acetate; Betamethasone Benzoate;    Betamethasone Dipropionate; Betamethasone Sodium Phosphate;    Betamethasone Valerate; Carbenoxolone Sodium; Clocortolone Acetate;    Clocortolone Pivalate; Cloprednol; Corticotropin; Corticotropin,    Repository; Corticotropin Zinc Hydroxide; Cortisone Acetate;    Cortivazol; Descinolone Acetonide; Dexamethasone; Dexamethasone    Sodium Phosphate; Diflucortolone; Diflucortolone Pivalate;    Flucloronide; Flumethasone; Flumethasone Pivalate; Flunisolide;    Fluocinolone Acetonide; Fluocinonide; Fluocortolone; Fluocortolone    Caproate; Fluorometholone; Fluperolone Acetate; Fluprednisolone;    Fluprednisolone Valerate; Flurandrenolide; Formocortal;    Hydrocortisone; Hydrocortisone Acetate; Hydrocortisone Buteprate;    Hydrocortisone Butyrate; Hydrocortisone Sodium Phosphate;    Hydrocortisone Sodium Succinate; Hydrocortisone Valerate; Medrysone;    Methylprednisolone; Methylprednisolone Acetate; Methylprednisolone    Sodium Phosphate; Methylprednisolone Sodium Succinate; Nivazol;    Paramethasone Acetate; Prednicarbate; Prednisolone; Prednisolone    Acetate; Prednisolone Hemisuccinate; Prednisolone Sodium Phosphate;    Prednisolone Sodium Succinate; Prednisolone Tebutate; Prednisone;    Prednival; Ticabesone Propionate; Tralonide; Triamcinolone;    Triamcinolone Acetonide; Triamcinolone Acetonide Sodium;    Triamcinolone Diacetate; Triamcinolone Hexacetonide.-   Gonad-stimulating principle: Buserelin Acetate; Clomiphene Citrate;    Ganirelix Acetate; Gonadorelin Acetate; Gonadorelin Hydrochloride;    Gonadotropin, Chorionic; Menotropins.-   Hair growth stimulant: Minoxidil.-   Hemostatic: Aminocaproic Acid; Oxamarin Hydrochloride; Sulmarin;    Thrombin; Tranexamic Acid.-   Histamine H2 receptor antagonists: Ranitidine (Zantac); Famotidine    (Pepcid); Cimetidine (Tagamet); Nizatidine (Axid).-   Hormone: Diethylstilbestrol; Progesterone; 17 hydroxy progesterone;    Medroxyprogesterone; Norgestrel; Norethynodrel; Estradiol; Megestrol    (Megace); Norethindrone; Levonorgestrel; Ethyndiol; Ethinyl    estradiol; Mestranol; Estrone; Equilin; 17 alpha dihydroequilin;    equilenin; 17 alpha dihydroequilenin; 17 alpha estradiol; 17 beta    estradiol; Leuprolide (lupron); Glucagon; Testolactone; Clomiphene;    Han menopausal gonadotropins; Human chorionic gonadotropin;    Urofollitropin; Bromocriptine; Gonadorelin; Luteinizing hormone    releasing hormone and analogs; Gonadotropins; Danazol; Testosterone;    Dehydroepiandrosterone; Androstenedione; Dihydroestosterone;    Relaxin; Oxytocin; Vasopressin; Folliculostatin; Follicle regulatory    protein; Gonadoctrinins; Oocyte maturation inhibitor; Insulin growth    factor; Follicle Stimulating Hormone; Luteinizing hormone;    Tamoxifen; Corticorelin Ovine Triffutate; Cosyntropin; Metogest;    Pituitary, Posterior; Seractide Acetate; Somalapor; Somatrem;    Somatropin; Somenopor; Somidobove.-   Hypocholesterolemic: Lifibrol.-   Hypoglycemic: Darglitazone Sodium; Glimepiride.-   Hypolipidemic: Azalanstat Dihydrochloride; Colestolone; Surfomer;    Xenalipin.-   Hypotensive: Viprostol.-   HMGCoA reductase inhibitors: Lovastatin (Mevacor); Simvastatin    (Zocor); Pravastatin (Pravachol); Fluvasatin (Lescol).-   Immunizing agent: Antirabies Serum; Antivenin (Latrodectus mactans);    Antivenin (Micrurus Fulvius); Antivenin (Crotalidae) Polyvalent; BCG    Vaccine; Botulism Antitoxin; Cholera Vaccine; Diphtheria Antitoxin;    Diphtheria Toxoid; Diphtheria Toxoid Adsorbed; Globulin, Immune;    Hepatitis B Immune Globulin; Hepatitis B Virus Vaccine Inactivated;    Influenza Virus Vaccine; Measles Virus Vaccine Live; Meningococcal    Polysaccharide Vaccine Group A; Meningococcal Polysaccharide Vaccine    Group C; Mumps Virus Vaccine Live; Pertussis Immune Globulin;    Pertussis Vaccine; Pertussis Vaccine Adsorbed; Plague Vaccine;    Poliovirus Vaccine Inactivated; Poliovirus Vaccine Live Oral; Rabies    Immune Globulin; Rabies Vaccine; Rh₀(D) Immune Globulin; Rubella    Virus Vaccine Live; Smallpox Vaccine; Tetanus Antitoxin; Tetanus    Immune Globulin; Tetanus Toxoid; Tetanus Toxoid Adsorbed; Typhoid    Vaccine; Yellow Fever vaccine; Vaccinia Immune Globulin;    Varicella-Zoster Immune Globulin.-   Immunomodulator: Dimepranol Acedoben; Imiquimod; Interferon Beta-1b;    Lisofylline; Mycophenolate Mofetil; Prezatide Copper Acetate.-   Immunoregulator: Azarole; Fanetizole Mesylate; Frentizole; Oxamisole    Hydrochloride; Ristianol Phosphate; Thymopentin; Tilomisole.-   Immunostimulant: Loxoribine; Teceleukin.-   Immunosuppressant: Azathioprine; Azathioprine Sodium; Cyclosporine;    Daltroban; Gusperimus Trihydrochloride; Sirolimus; Tacrolimus.-   Impotence therapy adjunct: Delequanine Hydrochloride.-   Inhibitor: Acarbose; Atorvastatin Calcium; Benserazide; Brocresine;    Carbidopa; Clavulanate Potassium; Dazmegrel; Docebenone;    Epoprostenol; Epoprostenol Sodium; Epristeride; Finasteride;    Flurbiprofen Sodium; Furegrelate Sodium; Lufironil; Miglitol;    Orlistat; Pimagedine Hydrochloride; Pirmagrel; Ponalrestat;    Ridogrel; Sulbactam Benzathine; Sulbactam Pivoxil; Sulbactam Sodium;    Suronacrine Maleate; Tazobactam; Tazobactam Sodium; Ticlopidine    Hydrochloride; Tirilazad Mesylate; Tolrestat; Velnacrine Maleate;    Zifrosilone; Zileuton.-   Keratolytic: Alcloxa; Aldioxa; Benzoyl Peroxide; Dibenzothiophene;    Etarotene; Isotretinoin; Motretinide; Picotrin Diolamine;    Resorcinol; Resorcinol Monoacetate; Salicylic Acid; Sumarotene;    Tazarotene; Tetroquinone; Tretinoin.-   LHRH agonist: Deslorelin; Goserelin; Histrelin; Lutrelin Acetate;    Nafarelin Acetate.-   Liver disorder treatment: Malotilate.-   Luteolysin: Fenprostalene.-   Memory adjuvant: Dimoxamine Hydrochloride; Ribaminol.-   Mental performance enhancer: Aniracetam.-   Mood regulator: Fengabine.-   Mucolytic: Acetylcysteine; Carbocysteine; Domiodol.-   Mucosal Protective agents: Misoprostol (Cytotec).-   Mydriatic: Berefrine.-   Nasal decongestant: Nemazoline Hydrochloride; Pseudoephedrine    Polistirex.-   Neuroleptic: Duoperone Furnarate; Risperidone.-   Neuromuscular blocking agent: Atracurium Besylate; Cisatracurium    Besylate; Doxacurium Chloride; Gallamine Triethiodide; Metocurine    Iodide; Mivacurium Chloride; Pancuronium Bromide; Pipecuronium    Bromide; Rocuronium Bromide; Succinylcholine Chloride; Tubocurarine    Chloride; Vecuronium Bromide.-   Neuroprotective: Dizocilpine Maleate.-   NMDA antagonist: Selfotel.-   Non-hormonal sterol derivative: Pregnenolone Succinate.-   Oxytocic: Carboprost; Carboprost Methyl; Carboprost Tromethamine;    Dinoprost; Dinoprost Tromethamine; Dinoprostone; Ergonovine Maleate;    Meteneprost; Methylergonovine Maleate; Oxytocin; Sparteine Sulfate.-   Plasminogen activator: Alteplase; Urokinase.-   Platelet activating factor antagonist: Lexipafant.-   Platelet aggregation inhibitor: Acadesine; Beraprost; Beraprost    Sodium; Ciprostene Calcium; Itazigrel; Lifarizine; Oxagrelate.-   Post-stroke and post-head trauma treatment: Citicoline Sodium.-   Potentiator: Pentostatin; Talopram Hydrochloride.-   Progestin: Algestone Acetophenide; Amadinone Acetate; Anagestone    Acetate; Chlormadinone Acetate; Cingestol; Clogestone Acetate;    Clomegestone Acetate; Desogestrel; Dimethisterone; Dydrogesterone;    Ethynerone; Ethynodiol Diacetate; Etonogestrel; Flurogestone    Acetate; Gestaclone; Gestodene; Gestonorone Caproate; Gestrinone;    Haloprogesterone; Hydroxyprogesterone Caproate; Levonorgestrel;    Lynestrenol; Medrogestone; Medroxyprogesterone Acetate; Methynodiol    Diacetate; Norethindrone; Norethindrone Acetate; Norethynodrel;    Norgestimate; Norgestomet; Norgestrel; Oxogestone Phenpropionate;    Progesterone; Quingestanol Acetate; Quingestrone; Tigestol.-   Prostaglandin: Cloprostenol Sodium; Fluprostenol Sodium; Gemeprost;    Prostalene; Sulprostone.-   Prostate growth inhibitor: Pentomone.-   Prothyrotropin: Protirelin.-   Psychotropic: Minaprine.-   Pulmonary surface: Beractant; Colfosceril Palmitate.-   Radioactive agent: Fibrinogen I 125; Fludeoxyglucose F 18;    Fluorodopa F 18; Insulin I 125; Insulin I 131; Iobenguane I 123;    Iodipamide Sodium I 131; Iodoantipyrine I 131; Iodocholesterol I    131; Iodohippurate Sodium I 123; Iodohippurate Sodium I 125    Iodohippurate Sodium I 131; Iodopyracet I 125; Iodopyracet I 131;    Iofetamine Hydrochloride I 123; Iomethin I125; Iomethin I 131;    Iothalamate Sodium I 125; Iothalamate Sodium I 131 Iotyrosine I 131;    Liothyronine I 125; Liothyronine I 131; Merisoprol Acetate Hg 197;    Merisoprol Acetate Hg 203; Merisoprol Hg 197; Selenomethionine Se    75; Technetium Tc 99m Antimony Trisulfide Colloid; Technetium Tc 99m    Bicisate; Technetium Tc 99m Disofenin; Technetium Tc 99m Etidronate;    Technetium Tc 99m Exametazime; Technetium Tc 99m Furifosmin;    Technetiumn Tc 99m Gluceptate; Technetium Tc 99m Lidofenin;    Technetium Tc 99m Mebrofenin; Technetium Tc 99m Medronate;    Technetium Tc 99m Medronate Disodium; Technetium Tc 99m Mertiatide;    Technetium Tc 99m Oxidronate; Technetium Tc 99m Pentetate;    Technetium Tc 99m Pentetate Calcium Trisodium; Technetium Tc 99m    Sestamibi; Technetium Tc 99m Siboroxime; Technetium Tc 99m Succimer;    Technetium Tc 99m Sulfur Colloid; Technetium Tc 99m Teboroxime;    Technetium Tc 99m Tetrofosmin; Technetium Tc 99m Tiatide; Thyroxine    I 125; Thyroxine I 131; Tolpovidone I 131; Triolein I 125; Triolein    I 131.-   Regulator: Calcifediol; Calcitonin; Calcitriol; Clodronic Acid;    Dihydrotachysterol; Etidronic Acid; Oxidronic Acid; Piridronate    Sodium; Risedronate Sodium; Secalciferol.-   Relaxant: Adiphenine Hydrochloride; Alcuronium Chloride;    Aminophylline; Azumolene Sodium; Baclofen; Benzoctamine    Hydrochloride; Carisoprodol; Chlorphenesin Carbamate; Chlorzoxazone;    Cinflumide; Cinnamedrine; Clodanolene; Cycloberzaprine    Hydrochloride; Dantrolene; Dantrolene Sodium; Fenalamide; Fenyripol    Hydrochloride; Fetoxylate Hydrochloride; Flavoxate Hydrochloride;    Fletazepam; Flumetramide; Flurazepam Hydrochloride; Hexafluorenium    Bromide; Isomylamine Hydrochloride; Lorbamate; Mebeverine    Hydrochloride; Mesuprine Hydrochloride; Metaxalone; Methocarbamol;    Methixene Hydrochloride; Nafomine Malate; Nelezaprine Maleate;    Papaverine Hydrochloride; Pipoxolan Hydrochloride; Quinctolate;    Ritodrine; Ritodrine Hydrochloride; Rolodine; Theophylline Sodium    Glycinate; Thiphenamil Hydrochloride; Xilobam.-   Repartitioning agent: Cimaterol.-   Scabicide: Amitraz; Crotaniton.-   Sclerosing agent: Ethanolamine Oleate; Morrhuate Sodium;    Tribenoside.-   Sedative: Propiomazine.-   Sedative-hypnotic: Allobarbital; Alonimid; Alprazolam; Amobarbital    Sodium; Bentazepam; Brotizolam; Butabarbital; Butabarbital Sodium;    Butalbital; Capuride; Carbocloral; Chloral Betaine; Chloral Hydrate;    Chlordiazepoxide Hydrochloride; Cloperidone Hydrochloride;    Clorethate; Cyprazepam; Dexclamol Hydrochloride; Diazepam;    Dichloralphenazone; Estazolam; Ethchlorvynol; Etomidate; Fenobam;    Flunitrazepam; Fosazepam; Glutethimide; Halazeparn; Lormetazepam;    Mecloqualone; Meprobamate; Methaqualone; Midaflur; Paraldehyde;    Pentobarbital; Pentobarbital Sodium; Perlapine; Prazepam; Quazepam;    Reclazepam; Roletamide; Secobarbital; Secobarbital Sodium;    Suproclone; Thalidomide; Tracazolate; Trepipam Maleate; Triazolam;    Tricetamide; Triclofos Sodium; Trimetozine; Uldazepam; Zaleplon;    Zolazepam Hydrochloride; Zolpidem Tartrate.-   Selective adenosine A1 antagonist: Apaxifylline.-   Serotonin antagonist: Altanserin Tartrate; Amesergide; Ketanserin;    Ritanserin.-   Serotonin inhibitor: Cinanserin Hydrochloride; Fenclonine; Fonazine    Mesylate; Xylamidine Tosylate.-   Serotonin receptor antagonist: Tropanserin Hydrochloride.-   Steroid: Dexamethasone Acefurate; Mometasone Furoate.-   Stimulant: Amfonelic Acid; Amphetamine Sulfate; Ampyzine Sulfate;    Arbutamine Hydrochloride; Azabon; Caffeine; Ceruletide; Ceruletide    Diethylamine; Cisapride; Dazopride Fumarate; Dextroamphetamine;    Dextroamphetamine Sulfate; Difluanine Hydrochloride; Dimefline    Hydrochloride; Doxapram Hydrochloride; Etryptamine Acetate;    Ethamivan; Fenethylline Hydrochloride; Flubanilate Hydrochloride;    Flurothyl; Histamine Phosphate; Indriline Hydrochloride; Mefexamide;    Methamphetamine Hydrochloride; Methylphenidate Hydrochloride;    Pemoline; Pyrovalerone Hydrochloride; Xamoterol; Xamoterol Fumarate.-   Suppressant: Amflutizole; Colchicine; Tazofelone.-   Symptomatic multiple sclerosis: Fampridine.-   Synergist: Proadifen Hydrochloride.-   Thyroid hormone: Levothyroxine Sodium; Liothyronine Sodium; Liotrix.-   Thyroid inhibitor: Methimazole; Propylthiouracil.-   Thyromimetic: Thyromedan Hydrochloride.-   Tranquilizer: Bromazepam; Buspirone Hydrochloride; Chlordiazepoxide;    Clazolam; Clobazam; Clorazepate Dipotassium; Clorazepate    Monopotassium; Demoxepam; Dexmedetomidine; Enciprazine    Hydrochloride; Gepirone Hydrochloride; Hydroxyphenamate; Hydroxyzine    Hydrochloride; Hydroxyzine Pamoate; Ketazolam; Lorazepam; Lorzafone;    Loxapine; Loxapine Succinate; Medazepam Hydrochloride; Nabilone;    Nisobamate; Oxazepam; Pentabanate; Pirenperone; Ripazepam; Rolipram;    Sulazepam; Taciamine Hydrochloride; Temazepam; Triflubazam;    Tybamate; Valnoctamide.-   Amyotrophic lateral sclerosis agents: Riluzole.-   Cerebral ischemia agents: Dextrorphan Hydrochloride.-   Paget's disease agents: Tiludronate Disodium.-   Unstable angina agents: Tirofiban Hydrochloride.-   Uricosuric: Benzbromarone; Irtemazole; Probenecid; Sulfinpyrazone.-   Vasoconstrictor: Angiotensin Amide; Felypressin; Methysergide;    Methysergide Maleate.-   Vasodilator: Alprostadil; Azaclorzine Hydrochloride; Bamethan    Sulfate; Bepridil Hydrochloride; Buterizine; Cetiedil Citrate;    Chromonar Hydrochloride; Clonitrate; Diltiazem Hydrochloride;    Dipyridamole; Droprenilamine; Erythrityl Tetranitrate; Felodipine;    Flunarizine Hydrochloride; Fostedil; Hexobendine; Inositol    Niacinate; Iproxamine Hydrochloride; Isosorbide Dinitrate;    Isosorbide Mononitrate; Isoxsuprine Hydrochloride; Lidoflazine;    Mefenidil; Mefenidil Fumarate; Mibefradil Dihydrochloride;    Mioflazine Hydrochloride; Mixidine; Nafronyl Oxalate; Nicardipine    Hydrochloride; Nicergoline; Nicorandil; Nicotinyl Alcohol;    Nifedipine; Nimodipine; Nisoldipine; Oxfenicine; Oxprenolol    Hydrochloride; Pentaerythritol Tetranitrate; Pentoxifylline;    Pentrinitrol; Perhexiline Maleate; Pindolol; Pirsidomine;    Prenylamine; Propatyl Nitrate; Suloctidil; Terodiline Hydrochloride;    Tipropidil Hydrochloride; Tolazoline Hydrochloride; Xanthinol    Niacinate.-   Vulnerary: Allantoin.-   Wound healing agent: Ersofermin.-   Xanthine oxidase inhibitor: Allopurinol; Oxypurinol-   Other pharmaceutical agents include: 1-decpyrrolidinone;    1-dodecpyrrolidinone; 16-alpha fluoroestradiol; 16-epiestriol;    16alpha-gitoxin; 17alpha estradiol; 17beta estradiol;    1alpha-hydroxyvitamin D2; 2′-nor-cGMP; 20-epi-1,25 dihydroxyvitamin    D3; 22-oxacalcitriol; 2CVV; 3-isobutyl GABA; 6-FUDCA;    7-methoxytacrine; abamectin; abanoquil; abecarnil; abiraterone;    acadesine; acamprosate; acarbose; aceclofenac; acemannan;    acetomepregenol; acetyl-L-carnitine; acetylcysteine, N-;    acetylmethadol; acifran; acipimox; acitemate; acitretin;    aclarubicin; aclatonium; napadisilate; aconiazide; acrivastinet;    adafenoxate; adapalene; adatanserin; adecypenol; adefovir dipivoxil;    adelmidrol; ademetionine; adinazolam; adiposin; adozelesin;    adrafinil; alacepril; aladapcin; alaptide; albendazole; albolabrin;    aldecalmycin; aldesleukin; alendronic acid; alentemol; alfacalcidol;    alfuzosin; alglucerase; alinastine; alosetron; alpha idosone;    alprostadil; altretamine; altromycin B; ambamustine; amelometasone;    amesergide; amezinium metilsulfate; amfebutamone; amidox;    amifloxacin; amifostine; amiodarone; amisulpride; amlexanox;    amlodipine; amlodipine; ampiroxicam; amrinone; amrubicin; amsacrine;    amylin; amythiamicin; anagrelide; anakinra; ananain; anaritide;    anastrozole; andrographolide; anordrin; apadoline; apafant;    apaxifylline; aphidicolin glycinate; apraclonidine; aprosulate    sodium; aptiganel; apurinic acid; aranidipine; arbekacin; arbidol;    arbutamine; ardeparin sodium; arecatannin B1; argatroban;    aripiprazol; arotinolol; asimadoline; aspalatone; asperfuran;    aspoxicillin; astemizole; asulacrine; atamestane; atenolol, S-;    atevirdine; atosiban; atovaquone; atpenin B; atrimustine;    atrinositol; aureobasidin A; azadirachtine; azasetron; azatyrosine;    azelaic acid; azelastine; azelnidipine; azimilide; azithromycin;    azosemide; aztreonam; baccatin III; bacoside A; bacoside B;    bactobolamine; balazipone; balhimycin; balofloxacin; balsalazide;    bambuterol; baohuoside 1; barnidipine; basifungin; batebulast;    batimastat; beauvericin; becaplermin; becliconazole; befloxatone;    belfosdil; bellenamine; benflumetol; benidipine; benzisoxazole;    benzochlorins; benzoidazoxan; benzoylstaurosporine; benztropine;    bepridil; beractant; beraprost; berlafenone; bertosamil;    besipirdine; beta-alethine; betaclamycin B; betamipron; betaxolol;    betulinic acid; bevantolol; bicalutamide; bifemelane; bimakalim;    bimithil; binospirone; bioxalomycin alpha2; biriperone;    bis-benzimidazole A; bis-benzimidazole B; bisantrene; bisaramil;    bisaziridinylspermine; bisnafide; bisoprolol; bistramide D;    bistramide K; bistratene A; boldine; bopindolol; brefeldin;    breflate; brimonidine; bromfenac; bromperidol; bropirimine;    bucindolol; budesonide; budipine; budotitane; bunaprolast;    bunazosin; butenafine; buthionine sulfoximine; butixocort    propionate; cadexomer iodine; calanolide A; calcipotriol; calphostin    C; camonagrel; candesartan; candesartan cilexetil; candoxatril;    candoxatrilat; capecitabine; capromab; capsaicin; captopril;    carbazomycin C; carbetocin; carbovir; carboxamide-amino-triazole;    carboxyamidotriazole; carboxymethylated beta-1,3-glucan;    carperitide; carteolol; carumonam; carvedilol; carvotroline;    carzelesin; castanospermine; cebaracetam, cecropin B; cefcapene    pivoxil; cefdaloxime pentexil tosilate; cefdinir; cefditoren    pivoxil; cefepime; cefetamet; cefetamet pivoxil; cefixime;    cefluprenam; cefmetazole; cefminox; cefodizime; cefoselis;    cefotetan; cefotiam; cefotiam hexetil; cefozopran; cefpimizole;    cefpiramide; cefpirome; cefpodoxime proxetil; cefprozil; cefsulodin;    cefteram; ceftibuten; ceftriaxone; cefuroxime axetil; celastrol;    celikalim; celiprolol; cepacidine A; cericlamine; cerivastatin;    ceronapril; certoparin sodium; cetiedil; cetirizine;    chloroorienticin A; chloroorienticin B; chloroquinoxaline    sulfonamide; cibenzoline; cicaprost; ciclesonide; cicletanine;    cicloprolol; cidofovir; cilansetron; cilazapril; cilnidipine;    cilobradine; cilostazol; cimetropium bromide; cinitapride;    cinolazepam; cioteronel; ciprofibrate; ciprofloxacin; ciprostene;    cis-porphyrin; cisapride; cisatracurium besilate; cistinexine;    citalopram; citicoline; citreamicin alpha; cladribine;    clarithromycin; clausenamide; clebopride; clinafloxacin; clobazam;    clobetasone butyrate; clodronic acid; clomethiazole; clopidogrel;    clotrimazole; colestimide; colfosceril palmitate; collismycin A;    collismycin B; combretastatin A4; complestatin; conagenin;    contignasterol; contortrostatin; cosalane; costatolide; cotinine;    coumermycin A1; cucumariosid; curacin A; curdlan sulfate; curiosin;    cyclazosin; cyclic HPMPC; cyclobenzaprine; cyclobut A; cyclobut G;    cyclocapron; cycloplatam; cyclosin; cyclothialidine;    cyclothiazomycin; cypemycin; cyproterone; cytarabine ocfosfate;    cytochalasin B; dacliximab; dactimicin; daidzein; daidzin;    dalfopristin; dalteparin sodium; danaparoid; daphnodorin A;    dapiprazole; dapitant; darifenacin; darlucin A; darsidomine; ddUTP;    decitabine; deferiprone; deflazacort; dehydrodidemnin B;    dehydroepiandrosterone; delapril; delequamine; delfaprazine;    delmopinol; delphinidin; deoxypyridinoline; deprodone; depsidomycin;    deramciclane; dermatan sulfate; desflurane; desirudin; deslorelin;    desmopressin; desogestrel; desoxoamiodarone; detajmium bitartrate;    dexifosfamide; dexketoprofen; dexloxiglumide; dexmedetomidine;    dexpemedolac; dexrazoxane; dexsotalol; dextrin 2-sulphate;    dexverapamil; dezinamide; dezocine; diaziquone; diclofenac digolil;    diclofenac potassium; dicranin; didemnin B; didox; dienogest;    diethylhomospermine; diethylnorspermine; dihydrexidine;    dihydro-5-azacytidine; dimethyl prostaglandin A1;    dimethylhomospermine; dimiracetam; dioxamycin; diphencyprone;    diphenyl spiromustine; diprafenone; dipropylnorspermine;    dirithromycin; discodermolide; disulfiram; ditekiren; docarpamine;    docosanol, 1-; dofetilide; dolasetron; domitroban; dopexamine;    dorzolamide; dosmalfate; dotarizine; doxacurium chloride; doxazosin;    doxifluridine; doxofylline; draculin; draflazine; droloxifene;    dronabinol; drosperidone; drotaverine acephyllinate; droxicam;    ebiratide; ebrotidine; ebselen; ecabapide; ecabet; ecadotril;    ecdisteron; echicetin; echistatin; ecomustine; ecteinascidin 722;    ecteinascidin 729; ecteinascidin 743; edaravone; edelfosine;    edobacomab; edrecolomab; efegatran; eflornithine; efonidipine;    egualen; elcatonin; eletriptan; elgodipine; eliprodil; eltenac;    emakalim; emedastine; emiglitate; emitefur; emoctakin; enadoline    hydrochloride; enalapril; enazadrem; englitazone; enlimomab;    enoxacin; enoxaparin sodium; enoximone; entacapone; enterostatin;    epoprostenol; epoxymexrenone; epristeride; eprosartan; eptastigmine;    erdosteine; ersentilide; ersofermin; erythritol; esuprone;    etanidazole; etanterol; ethacizin; ethinylestradiol; etizolam;    etodolac; etoposide phosphate; etrabamine; everninomicin;    examorelin; exemestane; fadrozole; faeriefungin; famciclovir;    fampridine; fantofarone; faropenem; fasidotril; fasudil; fazarabine;    fedotozine; felbamate; fenofibrate; fenoldopam; fenretinide;    fenspiride; fenticonazole; fepradinol; ferpifosate sodium;    ferristene; ferrixan; ferumoxsil; fexofenadine; flavopiridol;    flecainide; flerobuterol; fleroxacin; flesinoxan; flezelastine;    flobufen; flomoxef; florfenicol; florifenine; flosatidil;    fluasterone; fluconazole; fludarabine; flumazenil; flumecinol;    flumequine; flunarizine; fluocalcitriol; fluorodaunorunicin    hydrochloride; fluoxetine, R-; fluoxetine, S-; fluparoxan;    flupirtine; flurbiprofen axetil; flurithromycin; fluticasone    propionate; flutrimazole; fluvastatin; fluvoxamine; forasartan;    forfenimex; formestane; formoterol; formoterol, R,R-; fosfomycin;    trometamol; fosinopril; fosphenytoin; fostriecin; fotemustine;    gabapentin; gadobenic acid; gadobutrol; gadodiamide;    gadodiamide-EOB-DTPA; gadolinium texaphyrin; gadoteric acid;    gadoteridol; gadoversetamide; galantamine; galdansetron; gallopamil;    galocitabine; gamolenic acid; ganirelix; gepirone; gestrinone;    girisopam; glaspimod; glaucocalyxin A; glutapyrone; glycopine;    glycopril; granisetron; grepafloxacin; halichondrin B; halofantrine;    halomon; halopredone; hatomamicin; hatomarubigin A; hatomarubigin B;    hatomarubigin C; hatomarubigin D; ibogaine; ibopamine; ibudilast;    illimaquinone; ilmofosine; ilomastat; iloperidone; iloprost;    imidapril; imidazenil; indinavir; indolidan; indometacin farnesil;    indometacin; tropine ester; indoramin; inocoterone; inogatran;    inolimomab; interferon alfa; interferon alfa-2a; interferon alfa-2b;    interferon alfa-N1; interferon alfa-n3; interferon beta; interferon    beta-1a1; interferon beta-1b; interferon gamma-1a; interferon    gamma-1b; interferon omega; interferon, consensus; interleukin-1;    interleukin-1 alpha; interleukin-1 beta; interleukin-10;    interleukin-11; interleukin-12; interleukin-12; interleukin-15;    interleukin-2; interleukin-3; interleukin-4; interleukin-5;    interleukin-7; interleukin-8; iobenguane; iobitridol; iodoamiloride;    iododoxorubicin; iofratol; iomeprol; iopentol; iopromide; iopyrol;    iotriside; ioversol; ioxilan; ipazilide; IpdR; ipenoxazone;    ipidacrine; ipomeanol, 4-; ipriflavone; ipsapirone; irbesartan;    irinotecan; irloxacin; irsogladine; irtemazole; isalsteine;    isbogrel; isepamicin; isobengazole; isofloxythepin;    isohomohalicondrin B; isopropyl unoprostone; isradipine; itameline;    itasetron; itopride; itraconazole; ketoprofen, R-; ketoprofen, S-;    ketorolac; lacidipine; lactitol; lactivicin; laennec; lafutidine;    lamellarin-N triacetate; lamifiban; lamivudine; lamotrigine;    lanoconazole; lanperisone; lanreotide; lansoprazole; latanoprost;    lateritin; laurocapram; lazabemide; lemefloxacin; lemildipine;    leminoprazole; lenercept; lenograstim; lentinan sulfate; leptin;    leptolstatin; lercanidipine; lerisetron; lesopitron; letrazuril;    letrozole; leucomyzin; leuprorelin; levcromakalim; levetiracetam;    levobetaxolol; levobunolol; levobupivacaine; levocabastine;    levocarnitine; levodropropizine; levofloxacin; levomoprolol;    levonorgestrel; levormeloxifene; levosimendan; levosulpiride;    linotroban; linsidomine; lintitript; lintopride; liothyronine    sodium; lirexapride; lisinopril; lobaplatin; lobucavir; lodoxamide;    lombricine; lomefloxacin; lomerizine; lometrexol; lonazolac;    lonidamine; loracarbef; loratadine; lorglumide; lomoxicam; losartan;    losigamone; losoxantrone; loteprednol; loviride; loxoribine;    lubeluzole; lurtotecan; luteinizing hormone; lutetium; luzindole;    lydicamycin; lysofylline; lysostaphin; magainin 2 amide; magnolol;    mallotochromene; mallotojaponin; malotilate; mangafodipir;    manidipine; maniwamycin A; mannostatin A; manumycin E; manumycin F;    mapinastine; marimastat; Martek 8708; Martek 92211; masoprocol;    maspin; massetolide; meterelin; methoxatone; methylhistamine,    R-alpha; methylinosine monophosphate; methylprednisolone aceponate;    methylprednisolone suleptanate; metipamide; metoclopramide;    metoprolol, S-; metrifonate; mibefradil; michellamine B; microcolin    A; midodrine; mifepristone; miglitol; milacemide; milameline;    mildronate; milnacipran; milrinone; miltefosine; minaprine;    miokamycin; mipragoside; mirfentanil; mirimostim; mirtazapine;    misoprostol; mitoguazone; mitolactol; mitonafide; mitoxantrone;    mivacurium chloride; mivazerol; mixanpril; mizolastine; mizoribine;    moclobemide; modafinil; moexipril; mofarotene; mofezolac;    molgramostim; mometasone; montirelin; mopidamol; moracizine;    mosapramine; mosapride; motilide; moxiraprine; moxonidine;    nadifloxacin; nadroparin calcium; nafadotride; nafamostat;    nafarelin; naftopidil; naglivan; nagrestip; nalmefene; naphterpin;    napsagatran; naratriptan; nartograstim; nasaruplase; nateplase;    niperotidine; niravoline; nisamycin; nisin; nisoldipine;    nitazoxanide; nitecapone; nitrendipine; nitrendipine, S-;    nitrofurantoin monohydrate; nitrullyn; nizatidine; ofloxacin;    okicenone; olanzapine; olopatadine; olprinone; olsalazine;    omeprazole; onapristone; ondansetron; ondansetron, R-; ontazolast;    oracin; otenzepad; oxaliplatin; oxamisole, oxandrolone; oxaprozin;    oxaunomycin; oxcarbazepine; oxiconazole; oxiracetam; oxodipine;    ozagrel; palauamine; palinavir; palmitoylrhizoxin; pamaqueside;    pamicogrel; pamidronic acid; panamesine; panaxytriol; panipenem;    panipenum; pannorin; panomifene; pantethine; pantoprazole;    parabactin; parnaparin sodium; paroxetine; parthenolide;    pazelliptine; pazufloxacin; pefloxacin; pegaspargase; peldesine;    pemedolac; pemirolast; penciclovir; pentafuside; pentamidine;    pentamorphone; pentigetide; pentosan; pentostatin; pentrozole;    perflubron; perfosfamide; pergolide; perindoprilat; perospirone;    phenaridine; phenazinomycin; phenserine; phensuccinal; phentolamine    mesilate; phenylacetate; phenylalanyl ketoconazole; picenadol;    picibanil; picroliv; picumeterol; pidotimod; pilocarpine    hydrochloride; pilsicainide; pimagedine; pimilprost; pimobendan;    pinacidil; pinocebrin; pioglitazone; pipecuronium bromide;    pirarubicin; piretanide; pirfenidone; piritrexim; pirlindole;    pirmagrel; pirmenol; pirodavir; pirodomast; piroxicam cinnamate;    propagermanium; propentofylline; propionylcanitine, L-; propiram;    propiram+paracetamol; propiverine; propyl bis-acridone;    prostaglandin J2; prostratin; protegrin; protosufloxacin;    prulifloxacin; pyrazoloacridine; quazepam; quetiapine; quiflapon;    quinagolide; quinapril; quinfamide; quinupristin; raloxifene;    raltitrexed; ramatroban; ramripril; ramosetron; ranelic acid;    ranitidine bismuth citrate; ranolazine; recainam; regavirumab;    relaxin; repirinast; resinferatoxin; reticulon; reviparin sodium;    revizinone; ricasetron; ridogrel; rifabutin; rifapentine; rifaximin;    rilopirox; riluzole; rimantadine; rimexolone; rimoprogin; riodipine;    ripisartan; risedronic acid; rispenzepine; risperidone; ritanserin;    ritipenem; ritipenem acoxil; ritolukast; ritonavir; rizatriptan    benzoate; rohitukine; rokitamycin; ropinirole; ropivacaine;    roquinimex; roxatidine; roxindole; roxithromycin; rubiginone B1;    ruboxyl; rufloxacin; rupatidine; ruzadolane; safingol; safironil;    saintopin; salbutamol, R-; salmeterol; salmeterol, R-salnacedin;    sameridine; sampatrilat; sanfetrinem; saprisartan; sapropterin;    saquinavir; SarCNU; sarcophytol A sargramostim; sarpogrelate;    saruplase; saterinone; satigrel; satumomab pendetide; selegiline;    selenium thiosemicarbazone; sematilide; semduramicin; semotiadil;    semustine; sermorelin; sertaconazole; sertindole; sertraline;    setiptiline; sevirumab; sevoflurane; sezolamide; silipide;    silteplase; simendan; simvastatin; sinitrodil; sinnabidol;    sipatrigine; sirolimus; sizofiran; somatomedin B; somatomedin C;    somatrem; somatropin; sonermin; sotalol; staurosporine; stavudine;    stepronin; stipiamide; stiripentol; stobadine; succibun; sucralfate;    sulfasalazine; sulfinosine; sulfoxamine; sulopenem; sultamicillin;    sultopride; sulukast; sumatriptan; symakalim; tandospirone; tapgen;    taprostene; tasosartan; tazanolast; tazarotene; teicoplanin;    telenzepine; tellurapyrylium; telmesteine; telmisartan; temocapril;    temoporfin; temozolomide; tenidap; teniposide; tenosal; tenoxicam;    tepirindole; tepoxalin; terazosin; terbinafine; terfenadine;    terflavoxate; terguride; terlakiren; terlipressin; terodiline;    tertatolol; testosterone buciclate; tetrachlorodecaoxide;    tetrazomine; thaliblastine; thalidomide; thiocoraline; thiofedrine;    thiomarinol; thioperamide; thyroid stimulating hormone; tiagabine;    tianeptine; tiapafant; tibolone; ticlopidine; tienoxolol; tilisolol;    tilnoprofen arbamel; tiludronic acid; tinzaparin sodium; tiotropium    bromide; tipredane; tiqueside; tirandalydigin; tirapazamine;    tirilazad; tirofiban; tiropramide; topsentin; torasemide;    toremifene; tosufloxacin; trafermin; trandolapril; traxanox;    tretinoin; tretinoin tocoferil; triacetyluridine; tricaprilin;    trichohyalin; trichosanthin, alpha; triciribine; trientine;    triflavin; trimegestone; triptorelin; troglitazone; trombodipine;    tropisetron; trospectomycin; trovafloxacin; trovirdine; tucaresol;    tulobuterol; tylogenin; urapidil; uridine triphosphate;    valaciclovir; valproate magnesium; valproate semisodium; valsartan;    vamicamide; vanadeine; vaninolol; vapreotide; variolin B; velaresol;    venlafaxine; veramine; verapamil, (S); verdins; veroxan;    verteporfin; vesnarinone; vexibinol; vigabatrin; vinburnine citrate;    vinburnine resinate; vinconate; vinorelbine; vinpocetine;    vinpocetine citrate; vintoperol; vinxaltine; voriconazole; vorozole;    voxergolide; xemilofiban; ximoprofen; yangambin; zabicipril;    zacopride; zacopride, R-; zafirlukast; zalcitabine; zaleplon;    zalospirone; zaltoprofen; zanamivir; zankiren; zanoterone;    zatebradine; zatosetron; zenarestat; zeniplatin; zifrosilone;    zilascorb; zileuton; zinostatin stimalamer; ziprasidone; zoledronic    acid; zolmitriptan; zolpidem; zonisamide; zopiclone; zopiclone, S-;    zopolrestat; zotepine.

The invention also embraces novel compositions of matter that arecovalent conjugates of DHA and pharmaceutical agents that are noncentralnervous system active agents. Noncentral nervous system active agentshave no function or use within the central nervous system. Their onlyuse is outside of the central nervous system. Such agents include alldrugs within certain of the foregoing categories and only some drugswithin other of the foregoing catagories. For example, the entirecatagory of blood glucose regulators have no use or function within thecentral nervous system. In contrast, certain anti-cancer agents areuseful in the central nervous system whereas others are not. Forexample, central nervous system cancers are not hormone dependent, and,therefore, an anti-cancer agent such as Tamoxifen which treats certainhormone dependent cancers is not useful in the central nervous system.Those skilled in the art will be able to identify readily thosecatagories and/or members of a catagory which are noncentral nervoussystem active agents. Among the foregoing compounds, the followingcatagories and/or members of the following catagories are noncentralnervous system active agents: adrenocortical steroid; adrenocorticalsuppressant; aldosterone antagonist; amino acid; anabolic; androgen;antagonist; anthelmintic; anti-acne agent; anti-adrenergic;anti-allergic; anti-amebic; anti-androgen; anti-anemic; anti-anginal;anti-arthritic; anti-asthmatic; anti-atherosclerotic; antibacterial;anticholelithic; anticholelithogenic; anticholinergic; anticoagulant;anticoccidal; antidiabetic; antidiarrheal; antidiuretic; antidote;anti-estrogen; antifibrinolytic; antifungal; antiglaucoma agent;antihemophilic; antihemorrhagic; antihistamine; antihyperlipidemia;antihyperlipoproteinemic; antihypertensive; antithypotensive;anti-infective; anti-infective, topical; anti-inflanmmatory;antikeratinizing agent; antimalarial; antimicrobial; antimitotic;antimycotic, antineoplastic, antineutropenic, antiparasitic;antiperistaltic, antipneumocystic; antiproliferative; antiprostatichypertrophy; antiprotozoal; antipruritic; antipsoriatic; antirheumatic;antischistosomal; antiseborrheic; antisecretory; antispasmodic;antithrombotic; antitussive; anti-ulcerative; anti-urolithic; antiviral;appetite suppressant; benign prostatic hyperplasia therapy agent; boneresorption inhibitor; bronchodilator; carbonic anhydrase inhibitor;cardiac depressant; cardioprotectant; cardiotonic; cardiovascular agent;choleretic; cholinergic; cholinergic agonist; cholinesterasedeactivator; coccidiostat; diagnostic aid; diuretic; ectoparasiticide;enzyme inhibitor; estrogen; fibrinolytic; free oxygen radical scavenger;glucocorticoid; gonad-stimulating principle; hair growth stimulant;hemostatic; hormone; hypocholesterolemic; hypoglycemic; hypolipidemic;hypotensive; immunizing agent; immunomodulator; immunoregulator;immunostimulant; immunosuppressant; impotence therapy adjunct;inhibitor; keratolytic; LHRH agonist; liver disorder treatment;luteolysin; mucolytic; mydriatic; nasal decongestant; neuromuscularblocking agent; non-hormonal sterol derivative; oxytocic; plasminogenactivator; platelet activating factor antagonist; platelet aggregationinhibitor; potentiator; progestin; prostaglandin; prostate growthinhibitor; prothyrotropin; pulmonary surface; radioactive agent;regulator; relaxant; repartitioning agent; scabicide; sclerosing agent;selective adenosine A1 antagonist; steroid; suppressant; symptomaticmultiple sclerosis; synergist; thyroid hormone; thyroid inhibitor;thyromimetic; amyotrophic lateral sclerosis agents; Paget's diseaseagents; unstable angina agents; uricosuric; vasoconstrictor;vasodilator; vulnerary; wound healing agent; xanthine oxidase inhibitor.

As used herein, a taxane is a molecule that possesses the followingtricyclic carbon-atom connectivity network, which may incorporatecarbon-carbon multiple bonds, and which through the involvement ofcarbon-atom-noncarbon-atom bonds may include substituents, functionalgroups, and additional rings.

A taxoid is a molecule structurally related to a taxane in which theabove taxane carbon-atom connectivity network is altered, for example,by cleavage of one or more of the carbocyclic rings, by deletion oraddition of carbon substituents, by connection of carbon atoms normallynot bonded to each other, by disconnection of carbon atoms normallybonded to each other, or by some other reorganization of or adjustmentto the taxane carbon-atom connectivity network, but in which one or morestructural features characteristic of the taxane carbon-atomconnectivity network are conserved.

The compounds useful in the invention may be delivered in the form ofanti-cancer cocktails. An anti-cancer cocktail is a mixture of any oneof the compounds useful with this invention with another anti-canceragent such as an anti-cancer drug, a cytokine, and/or supplementarypotentiating agent(s). The use of cocktails in the treatment of canceris routine. In this embodiment, a common administration vehicle (e.g.,pill, tablet, implant, injectable solution, etc.) would contain both theconjugate useful in this invention and the anti-cancer drug and/orsupplementary potentiating agent.

The compounds of the invention, when used in cocktails, are administeredin therapeutically effective amounts. A therapeutically effective amountwill be determined by the parameters discussed below; but, in any event,is that amount which establishes a level of the drug(s) in the area ofthe tumor which is effective in inhibiting the tumor growth.

When administered, the formulations of the invention are applied inpharmaceutically acceptable amounts and in pharmaceutically acceptablecompositions. Such preparations may routinely contain salts, bufferingagents, preservatives, compatible carriers, and optionally othertherapeutic ingredients. When used in medicine the salts should bepharmaceutically acceptable, but non-pharmaceutically acceptable saltsmay conveniently be used to prepare pharmaceutically acceptable saltsthereof and are not excluded from the scope of the invention. Suchpharmacologically and pharmaceutically acceptable salts include, but arenot limited to, those prepared from the following acids: hydrochloric,hydrobromic, sulphuric, nitric, phosphoric, maleic, acetic, salicylic,p-toluene sulfonic, tartaric, citric, methane sulfonic, formic, malonic,succinic, naphthalene-2-sulfonic, and benzene sulfonic. Also,pharmaceutically acceptable salts can be prepared as alkaline metal oralkaline earth salts, such as sodium, potassium or calcium salts.

Suitable buffering agents include: acetic acid and a salt (1–2% W/V);citric acid and a salt (1–3% W/V); boric acid and a salt (0.5–2.5% W/V);and phosphoric acid and a salt (0.8–2% W/V).

Suitable preservatives include benzalkonium chloride (0.003–0.03% W/V);chlorobutanol (0.3–0.9% W/V); parabens (0.01–0.25% W/V) and thimerosal(0.004–0.02% W/V).

The active compounds of the present invention may be a pharmaceuticalcomposition having a therapeutically effective amount of a conjugate ofthe invention optionally included in a pharmaceutically-acceptablecarrier. The term “pharmaceutically-acceptable carrier” as used hereinmeans one or more compatible solid or liquid filler, dilutants orencapsulating substances which are suitable for administration to ahuman or other animal. The term “carrier” denotes an organic orinorganic ingredient, natural or synthetic, with which the activeingredient is combined to facilitate the application. The components ofthe pharmaceutical compositions are capable of being commingled with themolecules of the present invention, and with each other, in a mannersuch that there is no interaction which would substantially impair thedesired pharmaceutical efficacy.

Compositions suitable for parenteral administration convenientlycomprise a sterile preparation of the conjugates of the invention. Thispreparation may be formulated according to known methods. Formulationsfor taxanes can be found in Chapter 9 of Taxol: Science andApplications, CRC Press, Inc., 2000 Corporate Boulevard, N.W., BocaRaton, Fla. 33431. In general, Taxol has been formulated as a 6 mg/mlcremophor EL (polyoxyethylated castor oil)/ethanol mixture, which isdiluted to final volume with normal saline or 5% dextrose. A 15 mg/mlsolution of taxotere has been formulated in polysorbate 80(polyoxyethylene sorbitanmonooleate)/ethanol mixture, diluted with 5%dextrose.

The sterile preparation thus may be a sterile solution or suspension ina non-toxic parenterally-acceptable diluent or solvent. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose any bland fixed oil may be employedincluding synthetic mono or di-glycerides. In addition, fatty acids suchas oleic acid find use in the preparation of injectables. Carrierformulations suitable for oral, subcutaneous, intravenous,intramuscular, etc. can be found in Remington's Pharmaceutical Sciences,Mack Publishing Company, Easton, Pa.

A subject as used herein means humans, primates, horses, cows, pigs,sheep, goats, dogs, cats and rodents.

The conjugates of the invention are administered in effective amounts.An effective amount means that amount necessary to delay the onset of,inhibit the progression of, halt altogether the onset or progression ofor diagnose the particular condition being treated. In general, aneffective amount for treating cancer will be that amount necessary toinhibit mammalian cancer cell proliferation in-situ. When administeredto a subject, effective amounts will depend, of course, on theparticular condition being treated; the severity of the condition;individual patient parameters including age, physical condition, sizeand weight; concurrent treatment; frequency of treatment; and the modeof administration. These factors are well known to those of ordinaryskill in the art and can be addressed with no more than routineexperimentation. It is preferred, generally that a maximum dose be used,that is, the highest safe dose according to sound medical judgment.

Dosage may be adjusted appropriately to achieve desired drug levels,locally or systemically. Generally, daily oral doses of active compoundswill be from about 0.01 mg/kg per day to 1000 mg/kg per day. It isexpected that IV doses in the range of about 1 to 1000 mg/m² per daywill be effective. In the event that the response in a subject isinsufficient at such doses, even higher doses (or effective higher dosesby a different, more localized delivery route) may be employed to theextent that patient tolerance permits. Continuous IV dosing over, forexample 24 hours or multiple doses per day are contemplated to achieveappropriate systemic levels of compounds.

A variety of administration routes are available. The particular modeselected will depend of course, upon the particular drug selected, theseverity of the disease state being treated and the dosage required fortherapeutic efficacy. The methods of this invention, generally speaking,may be practiced using any mode of administration that is medicallyacceptable, meaning any mode that produces effective levels of theactive compounds without causing clinically unacceptable adverseeffects. Such modes of administration include oral, rectal, sublingual,topical, nasal, transdermal or parenteral routes. The term “parenteral”includes subcutaneous, intravenous, intramuscular, or infusion.Intravenous routes are preferred.

The compositions may conveniently be presented in unit dosage form andmay be prepared by any of the methods well known in the art of pharmacy.All methods include the step of bringing the conjugates of the inventioninto association with a carrier which constitutes one or more accessoryingredients. In general, the compositions are prepared by uniformly andintimately bringing the compounds into association with a liquidcarrier, a finely divided solid carrier, or both, and then, ifnecessary, shaping the product.

Compositions suitable for oral administration may be presented asdiscrete units such as capsules, cachets, tablets, or lozenges, eachcontaining a predetermined amount of the active compound. Othercompositions include suspensions in aqueous liquors or non-aqueousliquids such as a syrup, an elixir, or an emulsion.

Other delivery systems can include time-release, delayed release orsustained release delivery systems. Such systems can avoid repeatedadministrations of the active compounds of the invention, increasingconvenience to the subject and the physician. Many types of releasedelivery systems are available and known to those of ordinary skill inthe art. They include polymer based systems such as polylactic andpolyglycolic acid, polyanhydrides and polycaprolactone; nonpolymersystems that are lipids including sterols such as cholesterol,cholesterol esters and fatty acids or neutral fats such as mono-, di andtriglycerides; hydrogel release systems; silastic systems; peptide basedsystems; wax coatings, compressed tablets using conventional binders andexcipients, partially fused implants and the like. In addition, apump-based hardware delivery system can be used, some of which areadapted for implantation.

A long-term sustained release implant also may be used. “Long-term”release, as used herein, means that the implant is constructed andarranged to deliver therapeutic levels of the active ingredient for atleast 30 days, and preferably 60 days. Long-term sustained releaseimplants are well known to those of ordinary skill in the art andinclude some of the release systems described above. Such implants canbe particularly useful in treating solid tumors by placing the implantnear or directly within the tumor, thereby affecting localized,high-doses of the compounds of the invention.

The conjugates of the invention also are useful, in general, fortreating mammalian cell proliferative disorders other than cancer,including psoriasis, actinic keratosis, etc. They further are useful intreating diabetes and its complications, excess acid secretion,cardiovascular conditions involving cholesterol (e.g., hyperlipidemiaand hypercholesterolemia), diarrhea, ovarian diseases (e.g.endometriosis, ovarian cysts, etc.) and as contraceptive agents.

Those skilled in the art will be able to recognize with no more thanroutine experimentation numerous equivalents to the specific productsand processes described above. Such equivalents are intended to beincluded within the scope of the appended claims.

1. A pharmaceutical preparation comprising: a covalent conjugate ofcis-docosahexaenoic acid and an agent, and a pharmaceutically acceptablecarrier, wherein the agent is selected from the group consisting ofcalcitriol, 22-oxacalcitriol, fluocalcitriol, calcipotriol,calcipotriene, calcifediol, secalciferol, dihydrotachysterol,20-epi-1,25 dihydroxyvitamin D3, 1 alpha-hydroxyvitamin D2, andalfacalcidol.
 2. The pharmaceutical preparation of claim 1, wherein theagent is calcitriol.
 3. The pharmaceutical preparation of claim 1,wherein the agent is 22-oxacalcitriol.
 4. The pharmaceutical preparationof claim 1, wherein the agent is fluocalcitriol.
 5. The pharmaceuticalpreparation of claim 1, wherein the agent is calcipotriol.
 6. Thepharmaceutical preparation of claim 1, wherein the agent iscalcipotriene.
 7. The pharmaceutical preparation of claim 1, wherein theagent is calcifediol.
 8. The pharmaceutical preparation of claim 1,wherein the agent is secalciferol.
 9. The pharmaceutical preparation ofclaim 1, wherein the agent is dihydrotachysterol.
 10. The pharmaceuticalpreparation of claim 1, wherein the agent is 20-epi-1,25dihydroxyvitamin D3.
 11. The pharmaceutical preparation of claim 1,wherein the agent is 1 alpha-hydroxyvitamin D2.
 12. The pharmaceuticalpreparation of claim 1, wherein the agent is alfacalcidol.